Compounds and therapeutical use thereof

ABSTRACT

Disclosed are 4-arylamino-quinazolines and analogs thereof effective as activators of caspases and inducers of apoptosis. The compounds of this invention are useful in the treatment of a variety of clinical conditions in which uncontrolled growth and spread of abnormal cells occurs.

RELATED U.S. APPLICATIONS

This application is a continuation of Ser. No. 11/620,498 filed Jan. 5,2007, which is a continuation of Ser. No. 10/885,903 filed Jul. 6, 2004and issued as U.S. Pat. No. 7,618,975, and this application claimsbenefit (under 35 U.S.C. §120) on the earlier filing date of prior U.S.Provisional Application Ser. No. 60/484,325 filed Jul. 3, 2003, U.S.Provisional Application Ser. No. 60/493,006 filed Aug. 7, 2003, U.S.Provisional Application Ser. No. 60/557,556, filed Mar. 29, 2004, andU.S. Provisional Application Ser. No. 60/571,288, filed May 14, 2004,the contents of each of which are incorporated herein by reference intheir entirety.

FIELD OF THE INVENTION

This invention is in the field of medicinal chemistry. In particular,the invention relates to compounds that are activators of caspases andinducers of apoptosis. The invention also relates to the use of thesecompounds as therapeutically effective anti-cancer agents.

TECHNICAL BACKGROUND

Organisms eliminate unwanted cells by a process variously known asregulated cell death, programmed cell death or apoptosis. Such celldeath occurs as a normal aspect of animal development, as well as intissue homeostasis and aging (Glucksmann, A., Biol. Rev. CambridgePhilos. Soc. 26:59-86 (1951); Glucksmann, A., Archives de Biologie76:419-437 (1965); Ellis, et al., Dev. 112:591-603 (1991); Vaux, et al.,Cell 76:777-779 (1994)). Apoptosis regulates cell number, facilitatesmorphogenesis, removes harmful or otherwise abnormal cells andeliminates cells that have already performed their function.Additionally, apoptosis occurs in response to various physiologicalstresses, such as hypoxia or ischemia (PCT published applicationWO96/20721).

There are a number of morphological changes shared by cells experiencingregulated cell death, including plasma and nuclear membrane blebbing,cell shrinkage (condensation of nucleoplasm and cytoplasm), organellerelocalization and compaction, chromatin condensation and production ofapoptotic bodies (membrane enclosed particles containing intracellularmaterial) (Orrenius, S., J. Internal Medicine 237:529-536 (1995)).

Apoptosis is achieved through an endogenous mechanism of cellularsuicide (Wyllie, A. H., in Cell Death in Biology and Pathology, Bowenand Lockshin, eds., Chapman and Hall (1981), pp. 9-34). A cell activatesits internally encoded suicide program as a result of either internal orexternal signals. The suicide program is executed through the activationof a carefully regulated genetic program (Wyllie, et al., Int. Rev. Cyt.68:251 (1980); Ellis, et al., Ann. Rev. Cell Bio. 7:663 (1991)).Apoptotic cells and bodies are usually recognized and cleared byneighboring cells or macrophages before lysis. Because of this clearancemechanism, inflammation is not induced despite the clearance of greatnumbers of cells (Orrenius, S., J. Internal Medicine 237:529-536(1995)).

It has been found that a group of proteases are a key element inapoptosis (see, e.g., Thornberry, Chemistry and Biology 5:R97-R103(1998); Thornberry, British Med. Bull. 53:478-490 (1996)). Geneticstudies in the nematode Caenorhabditis elegans revealed that apoptoticcell death involves at least 14 genes, 2 of which are the pro-apoptotic(death-promoting) ced (for cell death abnormal) genes, ced-3 and ced-4.CED-3 is homologous to interleukin 1 beta-converting enzyme, a cysteineprotease, which is now called caspase-1. When these data were ultimatelyapplied to mammals, and upon further extensive investigation, it wasfound that the mammalian apoptosis system appears to involve a cascadeof caspases, or a system that behaves like a cascade of caspases. Atpresent, the caspase family of cysteine proteases comprises 14 differentmembers, and more may be discovered in the future. All known caspasesare synthesized as zymogens that require cleavage at an aspartyl residueprior to forming the active enzyme. Thus, caspases are capable ofactivating other caspases, in the manner of an amplifying cascade.

Apoptosis and caspases are thought to be crucial in the development ofcancer (Apoptosis and Cancer Chemotherapy, Hickman and Dive, eds.,Humana Press (1999)). There is mounting evidence that cancer cells,while containing caspases, lack parts of the molecular machinery thatactivates the caspase cascade. This makes the cancer cells lose theircapacity to undergo cellular suicide and the cells become cancerous. Inthe case of the apoptosis process, Control points are known to existthat represent points for intervention leading to activation. Thesecontrol points include the CED-9-BCL-like and CED-3-ICE-like gene familyproducts, which are intrinsic proteins regulating the decision of a cellto survive or die and executing part of the cell death process itself,respectively (see, Schmitt, et al., Biochem. Cell. Biol. 75:301-314(1997)). BCL-like proteins include BCL-xL and BAX-alpha, which appear tofunction upstream of caspase activation. BCL-xL appears to preventactivation of the apoptotic protease cascade, whereas BAX-alphaaccelerates activation of the apoptotic protease cascade.

It has been shown that chemotherapeutic (anti-cancer) drugs can triggercancer cells to undergo suicide by activating the dormant caspasecascade. This may be a crucial aspect of the mode of action of most, ifnot all, known anticancer drugs (Los, et al., Blood 90:3118-3129 (1997);Friesen, et al., Nat. Med. 2:574 (1996)). The mechanism of action ofcurrent antineoplastic drugs frequently involves an attack at specificphases of the cell cycle. In brief, the cell cycle refers to the stagesthrough which cells normally progress during their lifetime. Normally,cells exist in a resting phase termed G_(o). During multiplication,cells progress to a stage in which DNA synthesis occurs, termed S.Later, cell division, or mitosis occurs, in a phase called M.Antineoplastic drugs, such as cytosine arabinoside, hydroxyurea,6-mercaptopurine, and methotrexate are S phase specific, whereasantineoplastic drugs, such as vincristine, vinblastine, and paclitaxelare M phase specific. M phase specific antineoplastic drugs, such asvinblastine and paclitaxel, are known to affect tubulin polymerization.The ability of cells to appropriately polymerize and depolymerizetubulin is thought to be an important activity for M phase celldivision.

Many slow growing tumors, e.g. colon cancers, exist primarily in theG_(o) phase, whereas rapidly proliferating normal tissues, for examplebone marrow, exist primarily in the S or M phase. Thus, a drug like6-mercaptopurine can cause bone marrow toxicity while remainingineffective for a slow growing tumor. Further aspects of thechemotherapy of neoplastic diseases are known to those skilled in theart (see, e.g., Hardman, et al., eds., Goodman and Gilman's ThePharmacological Basis of Therapeutics, Ninth Edition, McGraw-Hill, NewYork (1996), pp. 1225-1287). Thus, it is clear that the possibilityexists for the activation of the caspase cascade, although the exactmechanisms for doing so are not clear at this point. It is equally clearthat insufficient activity of the caspase cascade and consequentapoptotic events are implicated in various types of cancer. Thedevelopment of caspase cascade activators and inducers of apoptosis is ahighly desirable goal in the development of therapeutically effectiveantineoplastic agents. Moreover, since autoimmune disease and certaindegenerative diseases also involve the proliferation of abnormal cells,therapeutic treatment for these diseases could also involve theenhancement of the apoptotic process through the administration ofappropriate caspase cascade activators and inducers of apoptosis.

EP520722 discloses derivatives of 4-anilino-quinazolines as inhibitorsof the EGFR tyrosine kinase with antitumor activity:

wherein, for example, R^(a) is hydrogen, trifluoromethyl, or nitro, n is1; and R^(b) is halogen, trifluoromethyl or nitro.

EP602851 discloses quinazolines as inhibitors of the EGFR tyrosinekinase:

wherein, for example R^(a) is hydroxy, amino, ureido, ortrifluoromethoxy, m is 1, 2 or 3; Q is a 9 or 10-membered bicyclicheterocyclic moiety.

EP635498 discloses 4-anilino-quinazolines as inhibitors of the EGFRtyrosine kinase:

wherein, for example R₁ includes hydroxy, amino or C₁₋₄ alkoxy, R₂ ishydrogen, hydroxy, or halogen, R₃ is halogen, n is 1, 2 or 3.

EP635507 discloses tricyclic derivatives as inhibitors of the EGFRtyrosine kinase:

wherein, R₁ and R₂ together form an optionally substituted 5 or 6membered ring containing at least one heteroatom; R₃ includes hydrogen,hydroxy, or halogen, m is 1, 2 or 3.

WO9609294 discloses substituted heteroaromatic compounds as inhibitorsof protein tyrosine kinase:

wherein, for example X is N or CH; Y is O, S, or NR^(a) wherein R^(a) isH or C₁₋₈ alkyl; R₁, R₂, R₃ and R_(3′) includes amino, hydrogen,hydroxy, or halogen; R₄ includes amino, hydrogen, hydroxy, or halogen; nis 1, 2 or 3; R₅ is selected from the group comprising hydrogen,halogen, trifluoromethyl, C₁₋₄ alkyl and C₁₋₄ alkoxy; R₆ is a group ZR₇wherein Z includes O, S or NH and R₇ is an optionally substituted C₃₋₆cycloalkyl, or an optionally substituted 5,6,7,8,9,10-memberedcarbocyclic or heterocyclic moiety.

WO9713771 discloses substituted heteroaromatic compounds as inhibitorsof protein tyrosine kinase:

wherein, for example X is N or CH; U represents a fused 5,6,7-memberedheterocyclic ring; Y is O, S, or NR^(a) wherein R^(a) is H or C₁₋₈alkyl; R₁ included 5,6-membered heterocyclic ring, or amino, hydrogen,hydroxy, or halogen; n is 0, 1, 2 or 3. R₂ is selected from the groupcomprising hydrogen, halogen, trifluoromethyl, C₁₋₄ alkyl and C₁₋₄alkoxy; R₃ is a group ZR₄ wherein Z includes O, S or NH and R₄ is anoptionally substituted C₃₋₆ cycloalkyl, or an optionally substituted5,6,7,8,9,10-membered carbocyclic or heterocyclic moiety. R₅ includeshydrogen, hydroxy, or halogen; n is 1, 2 or 3.

WO9802438 discloses bicyclic heteroaromatic compounds as inhibitors ofprotein tyrosine kinase:

wherein, for example X is N or CH; Y is O, S, or NR^(a) wherein R^(a) isH or C₁₋₈ alkyl; R″ represents a phenyl group or a 5- or 6-memberedheterocyclic ring, or amino, hydrogen, hydroxy, or halogen; n is 0 or 1.R₁ includes amino, hydrogen, hydroxy, or halogen; p is 0 to 3. R₂ isselected from the group comprising hydrogen, halogen, trifluoromethyl,C₁₋₄ alkyl and C₁₋₄ alkoxy; U represents a 5 to 10-membered mono orbicyclic ring system; A represents a fused 5, 6, or 7-memberedheterocyclic ring.

Myers et al. (Bioorg. Med. Chem. Lett. 7:421-424 (1997)) reported4-(N-methyl-N-phenyl)amino-6,7-dimethoxyquinazoline as inhibitor ofCSF-1R tyrosine kinase. It was reported that substitutions on the phenylring resulted in reduced activity. Replacement of the 6,7-dimethoxygroups by hydrogen resulted in more than 40-fold reduction in potency.Substitution in the 2-postion of quinazoline by a Cl or methoxy groupresulted in inactive compounds (IC₅₀>50 μM).

Rewcastle et al. (J. Med. Chem. 38:3482-3487 (1995)) reported4-(phenylamino)-quinazolines as inhibitors of tyrosine kinase ofEpidermal Growth Factor Receptor. It was reported that N-methylation ofthe amino group (R₁=Me, R₂═R₃═R₄═H) completely abolished activity(IC₅₀>100,000 nM). The 6,7-dimethoxy compound (R₁═H, R₂═R₃═OMe, R₄═Br,IC₅₀=0.029 nM) was almost 1000-fold more potent than the correspondingnon-substituted analog (R₁═H, R₂═R₃═H, R₄═Br, IC₅₀=27 nM).

Bridges et al. (J. Med. Chem. 39:267-276 (1996)) reported analogs of4-(3-bromoanilino)-6,7-dimethoxyquinazoline as inhibitors of tyrosinekinase of Epidermal Growth Factor Receptor. It was reported thatintroduction of a methyl group to the 2-position (R₁=Me, R₂=3′-Br, R₃═H)resulted in at least 400,000-fold loss of potency (IC₅₀>10,000 nM) vsthe hydrogen analog. Introduction of an amino group to the 2-position(R₁═NH₂, R₂=3′-Br, R₃═H) also resulted in over 18,000-fold loss ofpotency (IC₅₀>10,000 nM). Methylation of the anilino nitrogen (R₃=Me)led to 6,000-fold drop in activity. The 4′-Br analog (IC₅₀=0.96 nM) wasalmost 40-fold less active than the 3′-Br analog (IC₅₀=0.025 nM), andthe 2′-Br analog (IC₅₀=128 nM) was at least 5,000-fold less active thanthe 3′-Br analog.

SUMMARY OF THE INVENTION

The present invention is related to the discovery that4-arylamino-quinazolines and analogs, as represented in Formula I-VIbbelow, are potent tubulin inhibitors and active in inhibitingtopoisomerase, particularly topoisomerase II. They are activators of thecaspase cascade leading to the activation of caspase-3 and inducers orpromoters of apoptosis. Thus, they are useful in treating or delayingthe onset of diseases and disorders that are responsive to theinhibition of tubulin or topoisomerase, or to the induction ofapoptosis.

Accordingly, one aspect of the present invention is directed to the useof compounds of the present invention in inhibiting tubulin, in inducingcapase activities, particularly caspase-3 activities, in inhibitingtopoisomerase I or II, and inducing or promoting apoptosis, byadministering the compounds to cells in vitro or in vivo in warm-bloodanimals, particularly mammals.

Another aspect of the present invention is to provide a method fortreating or delaying the onset of diseases and disorders that areresponsive to inhibition of tubulin or topoisomerase II, including butnot limited to neoplastic diseases (such as cancer), psoriasis,autoimmune diseases, and fungi infection. The method comprisesadministering to a subject mammal in need of the treatment atherapeutically effective amount of a compound of the present invention.

Many of the compounds as represented by Formula I-VIb below are novelcompounds. Therefore, another aspect of the present invention is toprovide novel compounds, and to also provide for the use of these novelcompounds for treating, preventing or ameliorating neoplasia and cancer.

Yet another aspect of the present invention is to provide apharmaceutical composition useful for treating disorders responsive tothe inhibition of tubulin or topoisomerase II, and the induction ofapoptosis, containing an effective amount of a compound of the presentinvention, preferably in admixture with one or more pharmaceuticallyacceptable carriers or diluents.

In yet another aspect of the present invention, methods are provided forthe preparation of the novel compounds of the present invention.

The foregoing and other advantages and features of the invention, andthe manner in which the same are accomplished, will become more readilyapparent upon consideration of the following detailed description of theinvention taken in conjunction with the accompanying examples, whichillustrate preferred and exemplary embodiments.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts the results of a Topoisomerase II activity assay testingExample 1 compound;

FIG. 2 shows the results of a Topoisomere I activity assay testingExample 1 compound;

FIG. 3 depicts the binding of radiolabeled Example 102 compound toTopoisomerase II.

DETAILED DESCRIPTION OF THE INVENTION

It has been discovered that compounds of the present invention arepotent inhibitors of tubulin. It is also discovered that the compoundscan also inhibit topoisomerase activities, such as topoisomeraseII-dependent conversion of supercoiled DNA to topoisomers. The compoundsare potent and highly efficacious activators of the caspase cascadeparticularly caspase-3, and inducers of apoptosis. Therefore, thecompounds are useful for treating diseases and disorders responsive toinduction of apoptosis, inhibition of tubulin and/or inhibition oftopoisomerase II.

Thus, the present invention provides a method of inhibiting tubulin incells in vitro or in warm-blood animals, particularly mammals, moreparticularly humans. As used herein, the term “inhibiting tubulin” meansinhibiting the polymerization (or assembly) of tubulin monomers orpromoting depolymerization of microtubles (i.e., tubulin disassembly).Inhibition of tubulin can be assayed, e.g., by the method described inExample 145 below. The present invention also provides a method forinhibiting topoisomerase II in cells in vitro or in warm-blood animals,particularly mammals, more particularly humans. As used herein, the term“inhibiting topoisomerase II” means inhibiting the activities of theenzyme topoisomerase II in topoisomerase II-dependent conversion ofsupercoiled DNA to topoisomers. Inhibition of topoisomerase IIactivities can be assayed by, e.g., a method described in Example 151.In addition, the present invention also provides a method of activatingcaspase, particularly caspase-3 and inducing apoptosis in cells in vitroor in warm-blood animals, particularly mammals, more particularlyhumans. The term “activating caspase” as used herein means activating orenhancing the enzymatic (protease) activity of a caspase (e.g.,caspase-3), which, if occurring inside cells, results in promotedapoptosis or cell death. The ability of a compound in activatingcaspase, particularly caspase-3, can be assayed in a method as providedin Example 143 below. The term “inducing apoptosis” as used herein meansinducing apoptosis in cells so as to cause cell death. The ability of acompound to induce apoptosis can be tested in a method as described inExample 147 below. Also provided are methods for treating or delayingthe onset of diseases and disorders responsive to inhibiting tubulin,inhibiting topoisomerase II, activating caspase-3, or inducingapoptosis. Specific examples of such diseases and disorders are providedin details below.

The above various methods of the present invention can be practiced byor comprise treating cells in vitro or a warm-blood animal, particularlymammal, more particularly a human with an effective amount of a compoundaccording to the present invention. As used herein, the phrase “treating. . . with . . . a compound” means either administering the compound tocells or an animal, or administering to cells or an animal the compoundor another agent to cause the presence or formation of the compoundinside the cells or the animal. Preferably, the methods of the presentinvention comprise administering to cells in vitro or to a warm-bloodanimal, particularly mammal, more particularly a human a pharmaceuticalcomposition comprising an effective amount of a compound according tothe present invention.

Specifically, the methods of the present invention comprise treatingcells in vitro or a warm-blood animal, particularly mammal, moreparticularly a human with an effective amount of a compound according toFormula I:

or pharmaceutically acceptable salts or solvates thereof, wherein:

-   Ar is aryl or heteroaryl; each of which is optionally substituted by    one or more substituents wherein each substituent is independently    halo, hydroxy, hydroxy-C₁₋₆ alkyl-, C₁₋₆ alkyl-C(O)O—, amino, nitro,    cyano, C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₆ acylamino, C₁₋₆    acyloxy, C₁₋₆ alkoxy, or C₁₋₆ alkylthiol-;-   R₁ is C₁₋₆ alkyl, preferably methyl or ethyl, more preferably    methyl;-   A is an aromatic, heteroaromatic, heterocyclic, or carbocyclic ring;    each of which is optionally substituted by one or more substituents    wherein each substituent is as defined for Ar;-   R₂ is H, halo, nitro, cyano, azido, hydroxy, thiol, or a member of    the group consisting of: amino, alkoxy, C₁₋₆ alkyl, halo-C₁₋₆ alkyl,    C₂₋₆ alkenyl, C₂₋₆ alkynyl, hydroxyalkyl, amino-C₁₋₆ alkyl,    carboxy-C₁₋₆ alkyl, nitro, cyano, acylamido, acyloxy, carboxy,    carbonylamido, alkylthiol; each of which is optionally substituted    by one or more substituents wherein each substituent is as defined    for Ar;-   L is (CR₁₁R₁₂)n or NR₁₁CO wherein R₁₁ and R₁₂ independently are    hydrogen or alkyl optionally substituted by R_(1a), R_(1b), or    R_(1c); wherein R_(1a), R_(1b), and R_(1c) are as defined for Ar;-   n is 0, 1 or 2;-   B and D are independently nitrogen or CR₁₃, wherein R₁₃ is hydrogen,    halo, nitro, cyano, azido, hydroxy, thiol, or a member of the group    consisting of amino, alkoxy, C₁₋₆ alkyl, halo-C₁₋₆ alkyl, C₂₋₆    alkenyl, C₂₋₆ alkynyl, hydroxyalkyl, amino-C₁₋₆ alkyl, carboxy-C₁₋₆    alkyl, nitro, cyano, acylamido, acyloxy, carboxy, carbonylamido,    alkylthiol; each of which is optionally substituted by one or more    substituents wherein each substituent is as defined for Ar; and-   with the proviso that at least one of B and D is nitrogen.

Preferred compounds of Formula I include compounds wherein D isnitrogen, and B is CR₁₃. Other preferred compounds of Formula I includethose having Formula Ia:

or pharmaceutically acceptable salts or solvates thereof, wherein:

-   A ring is a 6-membered aryl, heteroaryl or carbocycle;-   L is [C(R_(L1))(R_(L2))]_(n) or —N(R_(L1))C(O)—, wherein R_(L1) and    R_(L2) independently are H or C₁₋₆ alkyl, n is 0, 1 or 2;-   R₁ is methyl or ethyl;-   Ar is aryl or heteroaryl, each of which is optionally substituted by    one or more substituents wherein each substituent is independently    H, halo, N₃, OH, thiol, nitro, CN, NH₂, C₁₋₆ alkyl, C₂₋₆ alkenyl,    C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ alkylthiol, halo-C₁₋₆ alkyl, C₂₋₆    alkenyl-O—, C₂₋₆ alkynyl-O—, hydroxy-C₁₋₆ alkyl, C₁₋₆ alkoxy-C₁₋₆    alkyl, C₁₋₆ acyl, C₁₋₆ acyloxy, —C₁₋₆ alkyl-C(O)O—C₁₋₆ alkyl,    —C(O)O—C₁₋₆ alkyl, C₁₋₆ alkyl-C(O)O—C₁₋₆ alkyl-, C₁₋₆ acylamido,    —N(R^(a))(R^(b)), —C₁₋₆ alkyl-C(O)N(R^(a))(R^(b)),    —C(O)N(R^(a))(R^(b)), N(R^(a))(R^(b))—C₁₋₆ alkyl-, 3, 4, 5, or    6-membered carbocycle, heterocycle, aryl, or heteroaryl, wherein    R^(a) and R^(b) are independently H, OH (R^(a) and R^(b) are not    both OH), C₂₋₆ hydroxyalkyl, or C₁₋₆ alkyl, or R^(a) and R^(b)    together with the nitrogen atom to which they are both linked form a    3, 4, 5 or 6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl,    and morpholinyl); wherein any of the groups is optionally    substituted with 1-3 substituents wherein each substituent is    independently halo, N₃, OH, thiol, nitro, CN, C₁₋₆ alkyl, C₂₋₆    alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ alkylthiol, C₂₋₆    alkenyl-O—, C₂₋₆ alkynyl-O—, hydroxy-C₁₋₆ alkyl, C₁₋₆ alkoxy-C₁₋₆    alkyl, C₁₋₆ acyl, C₁₋₆ acyloxy, —C₁₋₆ alkyl-C(O)O—C₁₋₆ alkyl,    —C(O)O—C₁₋₆ alkyl, C₁₋₆ alkyl-C(O)O—C₁₋₆ alkyl-, C₁₋₆ acylamido,    —N(R^(a))(R^(b)), —C₁₋₆ alkyl-C(O)N(R^(a))(R^(b)),    —C(O)N(R^(a))(R^(b)), N(Ra)(Rb)-C₁₋₆ alkyl, wherein R^(a) and R^(b)    are independently H, OH (R^(a) and R^(b) are not both OH), C₂₋₆    hydroxyalkyl, or C₁₋₆ alkyl or R^(a) and R^(b) together with the    nitrogen atom to which they are both linked form a 3, 4, 5 or    6-membered heterocycle;-   R₂-R₆, and R₁₂-R₁₇ are independently H, halo, N₃, OH, thiol, nitro,    CN, NH₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆    alkylthiol, halo-C₁₋₆ alkyl, C₂₋₆ alkenyl-O—, C₂₋₆ alkynyl-O—,    hydroxy-C₁₋₆ alkyl, C₁₋₆ alkoxy-C₁₋₆ alkyl, C₁₋₆ acyl, C₁₋₆ acyloxy,    —C₁₋₆ alkyl-C(O)O—C₁₋₆ alkyl, —C(O)O—C₁₋₆ alkyl, C₁₋₆    alkyl-C(O)O—C₁₋₆ alkyl-, C₁₋₆ acylamido, —N(R^(a))(R^(b)), —C₁₋₆    alkyl-C(O)N(R^(a))(R^(b)), —C(O)N(R^(a))(R^(b)),    N(R^(a))(R^(b))—C₁₋₆ alkyl, 3, 4, 5, or 6-membered carbocycle,    heterocycle, aryl, or heteroaryl, wherein R^(a) and R^(b) are    independently H, OH (R^(a) and R^(b) are not both OH), C₂₋₆    hydroxyalkyl, or C₁₋₆ alkyl, or R^(a) and R^(b) together with the    nitrogen atom to which they are both linked form a 3, 4, 5 or    6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and    morpholinyl); wherein any of the groups is optionally substituted    with 1-3 substituents wherein each substituent is independently    halo, N₃, OH, thiol, nitro, CN, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆    alkynyl, C₁₋₆ alkoxy, C₁₋₆ alkylthiol, C₂₋₆ alkenyl-O—, C₂₋₆    alkynyl-O—, hydroxy-C₁₋₆ alkyl, C₁₋₆ alkoxy-C₁₋₆ alkyl, C₁₋₆ acyl,    C₁₋₆ acyloxy, —C₁₋₆ alkyl-C(O)O—C₁₋₆ alkyl, —C(O)O—C₁₋₆ alkyl, C₁₋₆    alkyl-C(O)O—C₁₋₆ alkyl-, C₁₋₆ acylamido, —N(R^(a))(R^(b)), —C₁₋₆    alkyl-C(O)N(R^(a))(R^(b)), —C(O)N(R^(a))(R^(b)), N(Ra)(Rb)-C₁₋₆    alkyl, wherein R^(a) and R^(b) are independently H, OH (R^(a) and    R^(b) are not both OH), C₂₋₆ hydroxyalkyl, or C₁₋₆ alkyl or R^(a)    and R^(b) together with the nitrogen atom to which they are both    linked form a 3, 4, 5 or 6-membered heterocycle, with the proviso    that when A is aryl or heteroaryl, then there are no substituents    R₁₄-R₁₇; and-   B, D, Q, T, U and V, are independently carbon or nitrogen, wherein    at least one of B and D is nitrogen; wherein when B or D is    nitrogen, then there is no substituent at the nitrogen; and wherein    when A is heteroaryl and Q, T, U or V is nitrogen, then there is no    substituent at the nitrogen.

Preferably, when the A ring is aryl or heteroaryl and U is carbon, thenR₅ is hydrogen or flourine, preferably hydrogen.

Other preferred compounds include compounds wherein ring A is benzo orfused cyclohexyl. Another group of preferred compounds include compoundswherein Ar is phenyl, naphthyl, pyridyl, pyridazyl, pyrimidyl, pyrazyl,quinolyl, isoquinolyl, isoxazolyl, pyrazolyl, imidazolyl, thienyl, furylor pyrrolyl; each of which is optionally substituted by one or moresubstituents wherein each substituent is independently halo, hydroxy,hydroxyC₁₋₆ alkyl-, C₁₋₆ alkyl-C(O)O—, amino, nitro, cyano, C₁-C₆ alkyl,C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₁-C₆ acylamino, C₁-C₆ acyloxy, C₁-C₆alkoxy, or C₁₋₆ alkylthiol-. More preferably, Ar is phenyl, pyridyl,pyridazyl, pyrimidyl or pyrazyl, each of which is optionally substitutedby one or more substituents wherein each substituent is as definedimmediately above.

Another group of preferred compounds of Formula Ia include compoundswherein R₂ is H, halo, or a member of the group consisting of N₃, C₁₋₄alkoxy, C₁₋₄ alkylthiol, hydroxyC₁₋₄ alkyl, C₁₋₄ alkyl and—N(R^(a))(R^(b)) wherein R^(a) and R^(b) are independently H, OH (R^(a)and R^(b) are not both OH), C₂₋₄ hydroxyalkyl, or C₁₋₄ alkyl or R^(a)and R^(b) together with the nitrogen atom to which they are both linkedform a 3, 4, 5 or 6-membered heterocycle; each of the member isoptionally substituted by 1-4 substituents wherein each substituent isindependently halo, OH, or C₁₋₄ alkyl.

In preferred embodiments of the compounds of Formula Ia, one or two ofQ, T, U and V are nitrogen, and both B and D are nitrogen.

Other compounds of Formula I for use in the methods of the presentinvention include those having Formula Ib:

or pharmaceutically acceptable salts or solvates thereof,

-   wherein:-   R₁ is C₁₋₄ alkyl, preferably methyl or ethyl, more preferably    methyl;-   R₂-R₁₁ are independently H, halo, N₃, OH, thiol, nitro, CN, NH₂,    C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆    alkylthiol, halo-C₁₋₆ alkyl, C₂₋₆ alkenyl-O—, C₂₋₆ alkynyl-O—,    hydroxy-C₁₋₆ alkyl, C₁₋₆ alkoxy-C₁₋₆ alkyl, C₁₋₆ acyl, C₁₋₆ acyloxy,    —C₁₋₆ alkyl-C(O)O—C₁₋₆ alkyl, —C(O)O—C₁₋₆ alkyl, C₁₋₆    alkyl-C(O)O—C₁₋₆ alkyl-, C₁₋₆ acylamido, —N(R^(a))(R^(b)), —C₁₋₆    alkyl-C(O)N(R^(a))(R^(b)), —C(O)N(R^(a))(R^(b)),    N(R^(a))(R^(b))—C₁₋₆ alkyl-, 3, 4, 5, or 6-membered carbocycle,    heterocycle, aryl, or heteroaryl, wherein R^(a) and R^(b) are    independently H, OH (R^(a) and R^(b) are not both OH), C₂₋₆    hydroxyalkyl, or C₁₋₆ alkyl, or R^(a) and R^(b) together with the    nitrogen atom to which they are both linked form a 3, 4, 5 or    6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and    morpholinyl); wherein any of the groups is optionally substituted    with 1-3 substituents wherein each substituent is independently    halo, N₃, OH, thiol, nitro, CN, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆    alkynyl, C₁₋₆ alkoxy, C₁₋₆ alkylthiol, C₂₋₆ alkenyl-O—, C₂₋₆    alkynyl-O—, hydroxy-C₁₋₆ alkyl, C₁₋₆ alkoxy-C₁₋₆ alkyl, C₁₋₆ acyl,    C₁₋₆ acyloxy, —C₁₋₆ alkyl-C(O)O—C₁₋₆ alkyl, —C(O)O—C₁₋₆ alkyl, C₁₋₆    alkyl-C(O)O—C₁₋₆ alkyl-, C₁₋₆ acylamido, —N(R^(a))(R^(b)), —C₁₋₆    alkyl-C(O)N(R^(a))(R^(b)), —C(O)N(R^(a))(R^(b)),    N(R^(a))(R^(b))—C₁₋₆ alkyl-, wherein R^(a) and R^(b) are    independently H, OH (R^(a) and R^(b) are not both OH), C₂₋₆    hydroxyalkyl, or C₁₋₆ alkyl or R^(a) and R^(b) together with the    nitrogen atom to which they are both linked form a 3, 4, 5 or    6-membered heterocycle; wherein optionally two adjacent R₇-R₁₁    groups may together form a 3, 4, 5 or 6-membered aryl, heteroaryl,    carbocycle, or heterocycle.

Preferably, R₅ is H or F, more preferably H. Also preferably R₂ is R₂ isH, halo, or a member of the group consisting of: N₃, C₁₋₄ alkoxy, C₁₋₄alkylthiol, hydroxy-C₁₋₄ alkyl, C₁₋₄ alkyl and —N(R^(a))(R^(b)) whereinR^(a) and R^(b) are independently H, OH (R^(a) and R^(b) are not bothOH), C₂₋₄ hydroxyalkyl, or C₁₋₄ alkyl or R^(a) and R^(b) together withthe nitrogen atom to which they are both linked form a 3, 4, 5 or6-membered heterocycle (e.g., morpholino); each of the member isoptionally substituted by 1-4 substituents wherein each substituent isindependently halo, OH, or C₁₋₄ alkyl.

Other preferred compounds of Formula I for the methods of the inventioninclude those having Formula Ic:

or pharmaceutically acceptable salts or solvates thereof, wherein:

-   R₁ is C₁-₄ alkyl, preferably methyl or ethyl, more preferably    methyl;-   R₂-R₁₁ are independently H, halo, N₃, OH, thiol, nitro, CN, NH₂,    C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆    alkylthiol, halo-C₁₋₆ alkyl, C₂₋₆ alkenyl-O—, C₂₋₆ alkynyl-O—,    hydroxy-C₁₋₆ alkyl, C₁₋₆ alkoxy-C₁₋₆ alkyl, C₁₋₆ acyl, C₁₋₆ acyloxy,    —C₁₋₆ alkyl-C(O)O—C₁₋₆ alkyl, —C(O)O—C₁₋₆ alkyl, C₁₋₆    alkyl-C(O)O—C₁₋₆ alkyl-, C₁₋₆ acylamido, —N(R^(a))(R^(b)), —C₁₋₆    alkyl-C(O)N(R^(a))(R^(b)), —C(O)N(R^(a))(R^(b)),    N(R^(a))(R^(b))—C₁₋₆ alkyl-, 3, 4, 5, or 6-membered carbocycle,    heterocycle, aryl, or heteroaryl, wherein R^(a) and R^(b) are    independently H, OH (R^(a) and R^(b) are not both OH), C₂₋₆    hydroxyalkyl, or C₁₋₆ alkyl, or R^(a) and R^(b) together with the    nitrogen atom to which they are both linked form a 3, 4, 5 or    6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and    morpholinyl); wherein any of the groups is optionally substituted    with 1-3 substituents wherein each substituent is independently    halo, N₃, OH, thiol, nitro, CN, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆    alkynyl, C₁₋₆ alkoxy, C₁₋₆ alkylthiol, C₂₋₆ alkenyl-O—, C₂₋₆    alkynyl-O—, hydroxy-C₁₋₆ alkyl, C₁₋₆ alkoxy-C₁₋₆ alkyl, C₁₋₆ acyl,    C₁₋₆ acyloxy, —C₁₋₆ alkyl-C(O)O—C₁₋₆ alkyl, —C(O)O—C₁₋₆ alkyl, C₁₋₆    alkyl-C(O)O—C₁₋₆ alkyl-, C₁₋₆ acylamido, —N(R^(a))(R^(b)), —C₁₋₆    alkyl-C(O)N(R^(a))(R^(b)), —C(O)N(R^(a))(R^(b)),    N(R^(a))(R^(b))—C₁₋₆ alkyl-, wherein R^(a) and R^(b) are    independently H, OH (R^(a) and R^(b) are not both OH), C₂₋₆    hydroxyalkyl, or C₁₋₆ alkyl or R^(a) and R^(b) together with the    nitrogen atom to which they are both linked form a 3, 4, 5 or    6-membered heterocycle; wherein optionally two adjacent R₇-R₁₁    groups may together form a 3, 4, 5 or 6-membered aryl, heteroaryl,    carbocycle, or heterocycle.

Preferably, R₅ is H or F, more preferably H. Also preferably R₂ is H,halo, or a member of the group consisting of: N₃, C₁₋₄ alkoxy, C₁₋₄alkylthiol, hydroxy-C₁₋₄ alkyl, C₁₋₄ alkyl and —N(R^(a))(R^(b)) whereinR^(a) and R^(b) are independently H, OH (R^(a) and R^(b) are not bothOH), C₂₋₄ hydroxyalkyl, or C₁₋₄ alkyl or R^(a) and R^(b) together withthe nitrogen atom to which they are both linked form a 3, 4, 5 or6-membered heterocycle (e.g., morpholino); each of the member isoptionally substituted by 1-4 substituents wherein each substituent isindependently halo, OH, or C₁₋₄ alkyl.

Another group of compounds useful in the various methods of the presentinvention are those represented by Formula II:

or pharmaceutically acceptable salts or solvates thereof, wherein:

-   Ar is as defined in Formula Ia above;-   R₁ is a C₁₋₃ alkyl, preferably methyl or ethyl;-   R₂-R₆, R₁₂ and R₁₃ are independently H, halo, N₃, OH, thiol, nitro,    CN, NH₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆    alkylthiol, halo-C₁₋₆ alkyl, C₂₋₆ alkenyl-O—, C₂₋₆ alkynyl-O—,    hydroxy-C₁₋₆ alkyl, C₁₋₆ alkoxy-C₁₋₆ alkyl, C₁₋₆ acyl, C₁₋₆ acyloxy,    —C₁₋₆ alkyl-C(O)O—C₁₋₆ alkyl, —C(O)O—C₁₋₆ alkyl, C₁₋₆    alkyl-C(O)O—C₁₋₆ alkyl-, C₁₋₆ acylamido, —N(R^(a))(R^(b)), —C₁₋₆    alkyl-C(O)N(R^(a))(R^(b)), —C(O)N(R^(a))(R^(b)),    N(R^(a))(R^(b))—C₁₋₆ alkyl-, 3, 4, 5, or 6-membered carbocycle,    heterocycle, aryl, or heteroaryl, wherein R^(a) and R^(b) are    independently H, OH (R^(a) and R^(b) are not both OH), C₂₋₆    hydroxyalkyl, or C₁₋₆ alkyl, or R^(a) and R^(b) together with the    nitrogen atom to which they are both linked form a 3, 4, 5 or    6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and    morpholinyl); wherein any of the groups is optionally substituted    with 1-3 substituents wherein each substituent is independently    halo, N₃, OH, thiol, nitro, CN, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆    alkynyl, C₁₋₆ alkoxy, C₁₋₆ alkylthiol, C₂₋₆ alkenyl-O—, C₂₋₆    alkynyl-O—, hydroxy-C₁₋₆ alkyl, C₁₋₆ alkoxy-C₁₋₆ alkyl, C₁₋₆ acyl,    C₁₋₆ acyloxy, —C₁₋₆ alkyl-C(O)O—C₁₋₆ alkyl, —C(O)O—C₁₋₆ alkyl, C₁₋₆    alkyl-C(O)O—C₁₋₆ alkyl-, C₁₋₆ acylamido, —N(R^(a))(R^(b)), —C₁₋₆    alkyl-C(O)N(R^(a))(R^(b)), —C(O)N(R^(a))(R^(b)),    N(R^(a))(R^(b))—C₁₋₆ alkyl-, wherein R^(a) and R^(b) are    independently H, OH (R^(a) and R^(b) are not both OH), C₂₋₆    hydroxyalkyl, or C₁₋₆ alkyl or R^(a) and R^(b) together with the    nitrogen atom to which they are both linked form a 3, 4, 5 or    6-membered heterocycle; preferably, when U is C, R₅ is H or F,    preferably H; and-   B, D, Q, T, U and V are independently C or N, wherein at least one    of B and D is nitrogen. In some embodiments, at least one of Q, T, U    and V is N. In one embodiment, D is N and B is C. In another    embodiment, B is N and D is C. In another specific embodiment, both    B and D are N. In all embodiments, preferably when B, D, Q, T, U or    V is N, there is no substituent at the N.

Other preferred compounds include compounds wherein Ar is phenyl,naphthyl, pyridyl, pyridazyl, pyrimidyl, pyrazyl, quinolyl, isoquinolyl,isoxazolyl, pyrazolyl, imidazolyl, thienyl, furyl or pyrrolyl; each ofwhich is optionally substituted by one or more substituents wherein eachsubstituent is as defined immediately above. More preferably, Ar isphenyl, pyridyl or pyridazyl, pyrimidyl, pyrazyl, each of which isoptionally substituted by one or more substituents wherein eachsubstituent is as defined immediately above. Another group of preferredcompounds of Formula II include compounds wherein R₂ is a member of thegroup consisting of H, halo, N₃, C₁₋₄ alkoxy, C₁₋₄ alkylthiol,hydroxyC₁₋₄ alkyl, C₁₋₄ alkyl, and —N(R^(a))(R^(b)) wherein R^(a) andR^(b) are independently H, OH (R^(a) and R^(b) are not both OH), C₂₋₄hydroxyalkyl, or C₁₋₄ alkyl or R^(a) and R^(b) together with thenitrogen atom to which they are both linked form a 3, 4, 5 or 6-memberedheterocycle; each of the member being optionally substituted by 1-4substituents wherein each substituent is independently halo, OH, or C₁₋₄alkyl.

In preferred embodiments of the compounds of Formula II, one or two ofQ, T, U and V are N, and both B and D are N.

Another group of preferred compounds that may be employed in the methodsof the present invention are represented by Formula III:

or pharmaceutically acceptable salts or solvates thereof, wherein:

-   Ar is as defined above in Formula Ia and II;-   R₁ is a C₁₋₃ alkyl, preferably methyl or ethyl, more preferably    methyl;-   R₂-R₆ and R₁₂-R₁₇ are independently H, halo, N₃, OH, thiol, nitro,    CN, NH₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆    alkylthiol, halo-C₁₋₆ alkyl, C₂₋₆ alkenyl-O—, C₂₋₆ alkynyl-O—,    hydroxy-C₁₋₆ alkyl, C₁₋₆ alkoxy-C₁₋₆ alkyl, C₁₋₆ acyl, C₁₋₆ acyloxy,    —C₁₋₆ alkyl-C(O)O—C₁₋₆ alkyl, —C(O)O—C₁₋₆ alkyl, C₁₋₆    alkyl-C(O)O—C₁₋₆ alkyl-, C₁₋₆ acylamido, —N(R^(a))(R^(b)), —C₁₋₆    alkyl-C(O)N(R^(a))(R^(b)), —C(O)N(R^(a))(R^(b)),    N(R^(a))(R^(b))—C₁₋₆ alkyl, 3, 4, 5, or 6-membered carbocycle,    heterocycle, aryl, or heteroaryl, wherein R^(a) and R^(b) are    independently H, OH (R^(a) and R^(b) are not both OH), C₂₋₆    hydroxyalkyl, or C₁₋₆ alkyl, or R^(a) and R^(b) together with the    nitrogen atom to which they are both linked form a 3, 4, 5 or    6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and    morpholinyl); wherein any of the groups is optionally substituted    with 1-3 substituents wherein each substituent is independently    halo, N₃, OH, thiol, nitro, CN, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆    alkynyl, C₁₋₆ alkoxy, C₁₋₆ alkylthiol, C₂₋₆ alkenyl-O—, C₂₋₆    alkynyl-O—, hydroxy-C₁₋₆ alkyl, C₁₋₆ alkoxy-C₁₋₆ alkyl, C₁₋₆ acyl,    C₁₋₆ acyloxy, —C₁₋₆ alkyl-C(O)O—C₁₋₆ alkyl, —C(O)O—C₁₋₆ alkyl, C₁₋₆    alkyl-C(O)O—C₁₋₆ alkyl-, C₁₋₆ acylamido, —N(R^(a))(R^(b)), —C₁₋₆    alkyl-C(O)N(R^(a))(R^(b)), —C(O)N(R^(a))(R^(b)),    N(R^(a))(R^(b))—C₁₋₆ alkyl-, wherein R^(a) and R^(b) are    independently H, OH (R^(a) and R^(b) are not both OH), C₂₋₆    hydroxyalkyl, or C₁₋₆ alkyl or R^(a) and R^(b) together with the    nitrogen atom to which they are both linked form a 3, 4, 5 or    6-membered heterocycle; and-   B and D are independently C or N, wherein at least one of B and D is    N, and when B or D is N, then there is no substituent at the    nitrogen atom.

Other preferred compounds according to Formula III include compoundswherein Ar is phenyl, naphthyl, pyridyl, pyridazyl, pyrimidyl, pyrazyl,quinolyl, isoquinolyl, isoxazolyl, pyrazolyl, imidazolyl, thienyl, furylor pyrrolyl; each of which is optionally substituted by one or moresubstituents wherein each substituent is as defined immediately above.More preferably, Ar is phenyl, pyridyl pyridazyl, pyrimidyl, or pyrazyl,each of which is optionally substituted by one or more substituentswherein each substituent is as defined immediately above. In oneembodiment, Ar is pyridyl pyridazyl, pyrimidyl, or pyrazyl, each ofwhich is optionally substituted by one or more substituents as definedabove for Ar. Also preferably R₂ is a member of the group consisting ofH, halo, N₃, C₁₋₄ alkoxy, C₁₋₄ alkylthiol, hydroxyC₁₋₄ alkyl, C₁₋₄alkyl, and —N(R^(a))(R^(b)) wherein R^(a) and R^(b) are independently H,OH (R^(a) and R^(b) are not both OH), C₂₋₄ hydroxyalkyl, or C₁₋₄ alkylor R^(a) and R^(b) together with the nitrogen atom to which they areboth linked form a 3, 4, 5 or 6-membered heterocycle; each of the memberbeing optionally substituted by 1-4 substituents wherein eachsubstituent is independently halo, OH, or C₁₋₄ alkyl. In preferredembodiments of the compounds of Formula III, both B and D are N.

Preferably a compound according to Formula III is other than(5,6,7,8-tetrahydro-quinazolin-4-yl)-phenyl-ethyl-amine.

More preferably, the methods of inhibiting tubulin, inhibitingtopoisomerase II, activating caspase-3, inducing apoptosis and treatingor delaying the onset of diseases and disorders responsive to theinhibition of tubulin or topoisomerase II or to the activation ofcaspase-3 or induction of apoptosis comprise administering an effectiveamount of a compound or a pharmaceutical composition containing aneffective amount of the compound, which compound is represented by anyone of Formulae IV, IVa, IVb, V, Va, Vb, Vc, VI, VIa and VIb, and eachand all embodiments thereof and salts or solvates thereof, as providedbelow.

Additional compounds useful in such methods, particularly the methods ofinhibiting tubulin, inhibiting topoisomerase II, activating caspase-3and inducing apoptosis, and treating diseases and disorders responsiveto the inhibition of tubulin or topoisomerase II, or activatingcaspase-3 and inducing apoptosis include compounds according to FormulaIV:

and pharmaceutically acceptable salts and solvates thereof, wherein:

-   R₁ is methyl or ethyl, preferably methyl;-   A ring is a carbocycle, aryl or heteroaryl;-   R₂-R₁₇ are independently H, halo, N₃, OH, thiol, nitro, CN, NH₂,    C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆    alkylthiol, halo-C₁₋₆ alkyl, C₂₋₆ alkenyl-O—, C₂₋₆ alkynyl-O—,    hydroxy-C₁₋₆ alkyl, C₁₋₆ alkoxy-C₁₋₆ alkyl, C₁₋₆ acyl, C₁₋₆ acyloxy,    —C₁₋₆ alkyl-C(O)O—C₁₋₆ alkyl, —C(O)O—C₁₋₆ alkyl, C₁₋₆    alkyl-C(O)O—C₁₋₆ alkyl-, C₁₋₆ acylamido, —N(R^(a))(R^(b)), —C₁₋₆    alkyl-C(O)N(R^(a))(R^(b)), —C(O)N(R^(a))(R^(b)),    N(R^(a))(R^(b))—C₁₋₆ alkyl-, 3, 4, 5, or 6-membered carbocycle,    heterocycle, aryl, or heteroaryl, wherein R^(a) and R^(b) are    independently H, OH (R^(a) and R^(b) are not both OH), C₂₋₆    hydroxyalkyl, or C₁₋₆ alkyl, or R^(a) and R^(b) together with the    nitrogen atom to which they are both linked form a 3, 4, 5 or    6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and    morpholinyl); wherein any of the groups is optionally substituted    with 1-3 substituents wherein each substituent is independently    halo, N₃, OH, thiol, nitro, CN, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆    alkynyl, C₁₋₆ alkoxy, C₁₋₆ alkylthiol, C₂₋₆ alkenyl-O—, C₂₋₆    alkynyl-O—, hydroxy-C₁₋₆ alkyl, C₁₋₆ alkoxy-C₁₋₆ alkyl, C₁₋₆ acyl,    C₁₋₆ acyloxy, —C₁₋₆ alkyl-C(O)O—C₁₋₆ alkyl, —C(O)O—C₁₋₆ alkyl, C₁₋₆    alkyl-C(O)O—C₁₋₆ alkyl-, C₁₋₆ acylamido, —N(R^(a))(R^(b)), —C₁₋₆    alkyl-C(O)N(Ra)(Rb), —C(O)N(R^(a))(R^(b)), N(R^(a))(R^(b))—C₁₋₆    alkyl, wherein R^(a) and R^(b) are independently H, OH (R^(a) and    R^(b) are not both OH), C₂₋₆ hydroxyalkyl, or C₁₋₆ alkyl or R^(a)    and R^(b) together with the nitrogen atom to which they are both    linked form a 3, 4, 5 or 6-membered heterocycle, wherein optionally    any two adjacent R₇-R₁₁ groups together form a 3, 4, 5 or 6-membered    carbocycle or heterocycle, with the proviso that when A is aryl or    heteroaryl, then there are no substituents R₁₄-R₁₇; and-   B, D, Q, T, U, V, W, X, Y, and Z are independently C or N, wherein    at least one of B and D is N; wherein when B, D, W, X, Y, or Z is N,    then there is no sub stituent at the N; and wherein when A is    heteroaryl and Q, T, U or V is N, then there is no sub stituent at    the N.

Preferably when the A ring is aryl or heteroaryl and U is C, R₅ is notalkoxy. More preferably, when the A ring is aryl or heteroaryl and U isC, then R₅ is H or F, preferably H.

In some embodiments of the compounds of Formula IV, one of W, X, Y and Zis N. In other embodiments of the compounds of Formula IV, two of W, X,Y and Z are N. In any of the embodiments, preferably one or two of Q, T,U and V are N. In preferred embodiments, B and D both are N.

Further additional compounds in addition to the compounds represented byFormulae IV, IVa, IVb, V, Va, Vb, Vc, VI, VIa and VIb, and allembodiments thereof, which are useful in the methods of the presentinvention, particularly the methods of inhibiting tubulin, inhibitingtopoisomerase II, activating caspase-3 and inducing apoptosis, andtreating diseases and disorders responsive to the inhibition of tubulinor topoisomerase II, activating caspase-3 and inducing apoptosis,include compounds according to Formula VI:

or pharmaceutically acceptable salts or solvates thereof, wherein:

-   R₁ is methyl or ethyl, preferably methyl;-   R₅ is H or F, preferably H;-   R₂-R₄, R₆-R₁₃ are independently H, halo, N₃, OH, thiol, nitro, CN,    NH₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆    alkylthiol, halo-C₁₋₆ alkyl, C₂₋₆ alkenyl-O—, C₂₋₆ alkynyl-O—,    hydroxy-C₁₋₆ alkyl, C₁₋₆ alkoxy-C₁₋₆ alkyl, C₁₋₆ acyl, C₁₋₆ acyloxy,    —C₁₋₆ alkyl-C(O)O—C₁₋₆ alkyl, —C(O)O—C₁₋₆ alkyl, C₁₋₆    alkyl-C(O)O—C₁₋₆ alkyl-, C₁₋₆ acylamido, —N(R^(a))(R^(b)), —C₁₋₆    alkyl-C(O)N(R^(a))(R^(b)), —C(O)N(R^(a))(R^(b)),    N(R^(a))(R^(b))—C₁₋₆ alkyl, 3, 4, 5, or 6-membered carbocycle,    heterocycle, aryl, or heteroaryl, wherein R^(a) and R^(b) are    independently H, OH (R^(a) and R^(b) are not both OH), C₂₋₆    hydroxyalkyl, or C₁₋₆ alkyl, or R^(a) and R^(b) together with the    nitrogen atom to which they are both linked form a 3, 4, 5 or    6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and    morpholinyl); wherein any of the groups is optionally substituted    with 1-3 substituents wherein each substituent is independently    halo, N₃, OH, thiol, nitro, CN, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆    alkynyl, C₁₋₆ alkoxy, C₁₋₆ alkylthiol, C₂₋₆ alkenyl-O—, C₂₋₆    alkynyl-O—, hydroxy-C₁₋₆ alkyl, C₁₋₆ alkoxy-C₁₋₆ alkyl, C₁₋₆ acyl,    C₁₋₆ acyloxy, —C₁₋₆ alkyl-C(O)O—C₁₋₆ alkyl, —C(O)O—C₁₋₆ alkyl, C₁₋₆    alkyl-C(O)O—C₁₋₆ alkyl-, C₁₋₆ acylamido, —N(R^(a))(R^(b)), —C₁₋₆    alkyl-C(O)N(R^(a))(R^(b)), —C(O)N(R^(a))(R^(b)),    N(R^(a))(R^(b))—C₁₋₆ alkyl-, wherein R^(a) and R^(b) are    independently H, OH (R^(a) and R^(b) are not both OH), C₂₋₆    hydroxyalkyl, or C₁₋₆ alkyl or R^(a) and R^(b) together with the    nitrogen atom to which they are both linked form a 3, 4, 5 or    6-membered heterocycle, wherein optionally any two adjacent R₇-R₁₁    groups together form a 3, 4, 5 or 6-membered carbocycle or    heterocycle; and-   B, D, Q, T, U and V are independently C or N, provided that at least    one of B and D is N; wherein when B, D, Q, T, U or V is N, then    there is no sub stituent at the N.

In some embodiments of the compounds according to Formula VI, one or twoof Q, T, U and V are N. In preferred embodiments, both B and D are N.

Further additional compounds useful in such methods, particularly themethods of inhibiting tubulin, inhibiting topoisomerase II, activatingcaspase-3 and inducing apoptosis, and treating diseases and disordersresponsive to the inhibition of tubulin or topoisomerase II, activatingcaspase-3 and inducing apoptosis, include compounds according to FormulaVIa:

or pharmaceutically acceptable salts or solvates thereof, wherein:

-   R₁ is methyl or ethyl, preferably methyl;-   R₅ is H or F, preferably H;-   R₂-R₄, R₆-R₁₁ are independently H, halo, N₃, OH, thiol, nitro, CN,    NH₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆    alkylthiol, halo-C₁₋₆ alkyl, C₂₋₆ alkenyl-O—, C₂₋₆ alkynyl-O—,    hydroxy-C₁₋₆ alkyl, C₁₋₆ alkoxy-C₁₋₆ alkyl, C₁₋₆ acyl, C₁₋₆ acyloxy,    —C₁₋₆ alkyl-C(O)O—C₁₋₆ alkyl, —C(O)O—C₁₋₆ alkyl, C₁₋₆    alkyl-C(O)O—C₁₋₆ alkyl-, C₁₋₆ acylamido, —N(R^(a))(R^(b)), —C₁₋₆    alkyl-C(O)N(R^(a))(R^(b)), —C(O)N(Ra)(Rb), N(R^(a))(R^(b))—C₁₋₆    alkyl-, 3, 4, 5, or 6-membered carbocycle, heterocycle, aryl, or    heteroaryl, wherein R^(a) and R^(b) are independently H, OH (R^(a)    and R^(b) are not both OH), C₂₋₆ hydroxyalkyl, or C₁₋₆ alkyl, or    R^(a) and R^(b) together with the nitrogen atom to which they are    both linked form a 3, 4, 5 or 6-membered heterocycle (e.g.,    piperidinyl, pyrrolidinyl, and morpholinyl); wherein any of the    groups is optionally substituted with 1-3 substituents wherein each    substituent is independently halo, N₃, OH, thiol, nitro, CN, C₁₋₆    alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ alkylthiol,    C₂₋₆ alkenyl-O—, C₂₋₆ alkynyl-O—, hydroxy-C₁₋₆ alkyl, C₁₋₆    alkoxy-C₁₋₆ alkyl, C₁₋₆ acyl, C₁₋₆ acyloxy, —C₁₋₆ alkyl-C(O)O—C₁₋₆    alkyl, —C(O)O—C₁₋₆ alkyl, C₁₋₆ alkyl-C(O)O—C₁₋₆ alkyl-, C₁₋₆    acylamido, —N(R^(a))(R^(b)), —C₁₋₆ alkyl-C(O)N(Ra)(Rb),    —C(O)N(R^(a))(R^(b)), N(R^(a))(R^(b))—C₁₋₆ alkyl-, wherein R^(a) and    R^(b) are independently H, OH (R^(a) and R^(b) are not both OH),    C₂₋₆ hydroxyalkyl, or C₁₋₆ alkyl or R^(a) and R^(b) together with    the nitrogen atom to which they are both linked form a 3, 4, 5 or    6-membered heterocycle, wherein optionally any two adjacent R₇-R₁₁    groups together form a 3, 4, 5 or 6-membered carbocycle or    heterocycle; and-   Q, T, U and V are independently C or N, wherein when Q, T, U or V is    N, then there is no substituent at the N.

In some embodiments of the compounds according to Formula VIa, one ortwo of Q, T, U and V are N.

Still further additional compounds useful in such methods, particularlythe methods of inhibiting tubulin or topoisomerase II, activatingcaspase-3 and inducing apoptosis, and treating diseases and disordersresponsive to the inhibition of tubulin or topoisomerase II, activatingcaspase-3 and inducing apoptosis, include compounds according to FormulaVIb:

or pharmaceutically acceptable salts or solvates thereof, wherein:

-   R₁ is methyl or ethyl, more preferably methyl;-   R₅ is H or F, preferably H;-   R₂-R₄, R₆-R₁₁ are independently H, halo, N₃, OH, thiol, nitro, CN,    NH₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆    alkylthiol, halo-C₁₋₆ alkyl, C₂₋₆ alkenyl-O—, C₂₋₆ alkynyl-O—,    hydroxy-C₁₋₆ alkyl, C₁₋₆ alkoxy-C₁₋₆ alkyl, C₁₋₆ acyl, C₁₋₆ acyloxy,    —C₁₋₆ alkyl-C(O)O—C₁₋₆ alkyl, —C(O)O—C₁₋₆ alkyl, C₁₋₆    alkyl-C(O)O—C₁₋₆ alkyl-, C₁₋₆ acylamido, —N(R^(a))(R^(b)), —C₁₋₆    alkyl-C(O)N(R^(a))(R^(b)), —C(O)N(R^(a))(R^(b)),    N(R^(a))(R^(b))—C₁₋₆ alkyl-, 3, 4, 5, or 6-membered carbocycle,    heterocycle, aryl, or heteroaryl, wherein R^(a) and R^(b) are    independently H, OH (R^(a) and R^(b) are not both OH), C₂₋₆    hydroxyalkyl, or C₁₋₆ alkyl, or R^(a) and R^(b) together with the    nitrogen atom to which they are both linked form a 3, 4, 5 or    6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and    morpholinyl); wherein any of the groups is optionally substituted    with 1-3 substituents wherein each substituent is independently    halo, N₃, OH, thiol, nitro, CN, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆    alkynyl, C₁₋₆ alkoxy, C₁₋₆ alkylthiol, C₂₋₆ alkenyl-O—, C₂₋₆    alkynyl-O—, hydroxy-C₁₋₆ alkyl, C₁₋₆ alkoxy-C₁₋₆ alkyl, C₁₋₆ acyl,    C₁₋₆ acyloxy, —C₁₋₆ alkyl-C(O)O—C₁₋₆ alkyl, —C(O)O—C₁₋₆ alkyl, C₁₋₆    alkyl-C(O)O—C₁₋₆ alkyl-, C₁₋₆ acylamido, —N(R^(a))(R^(b)), —C₁₋₆    alkyl-C(O)N(R^(a))(R^(b)), —C(O)N(R^(a))(R^(b)),    N(R^(a))(R^(b))—C₁₋₆ alkyl-, wherein R^(a) and R^(b) are    independently H, OH (R^(a) and R^(b) are not both OH), C₂₋₆    hydroxyalkyl, or C₁₋₆ alkyl or R^(a) and R^(b) together with the    nitrogen atom to which they are both linked form a 3, 4, 5 or    6-membered heterocycle, wherein optionally any two adjacent R₇-R₁₁    groups together form a 3, 4, 5 or 6-membered carbocycle or    heterocycle.

In the various embodiments of the above methods of the presentinvention, preferably the compounds administered in the methods of theinvention are able to induce caspase activation as determined by themethod and under conditions (measurement at 24 hours) described inExample 143, preferably at an EC₅₀ no greater than 1,000 nM, morepreferably at an EC₅₀ no greater than about 500 nM, more preferably atan EC₅₀ no greater than about 200 nM, more preferably at an EC₅₀ nogreater than about 100 nM, even more preferably at an EC₅₀ no greaterthan about 50 nM, and most preferably at an EC₅₀ no greater than about10 nM. Also preferred in the above methods of the invention arecompounds of Formula I-VIb, and pharmaceutically acceptable salts orsolvates thereof, that are able to inhibit tubulin at an IC₅₀ of nogreater than about 2,000 nM, more preferably no greater than about 1,000nM, most preferably less than about 500 nM, as determined by the methodand under conditions described in Example 145.

Exemplary compounds useful in the methods of the invention include, butare not limited to, compounds in Examples 1-142; and pharmaceuticallyacceptable salts or solvates thereof, and:

-   (2-Chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;

(2-Chloro-quinazolin-4-yl)-(4-methyl-phenyl)-methyl-amine;

(2-Chloro-quinazolin-4-yl)-(4-chloro-phenyl)-methyl-amine;

(2-Chloro-quinazolin-4-yl)-(4-nitro-phenyl)-methyl-amine;

(2-Chloro-quinazolin-4-yl)-(4-trifluoromethoxy-phenyl)-methyl-amine;

(2-Chloro-quinazolin-4-yl)-phenyl-methyl-amine;

-   N²-Hydroxyl-N⁴-(4-methoxy-phenyl)-N⁴-methyl-quinazoline-2,4-diamine;-   N²-(2-Hydroxyl    ethyl)-N⁴-(4-methoxy-phenyl)-N⁴-methyl-quinazoline-2,4-diamine;-   N⁴-(4-methoxy-phenyl)-N⁴-methyl-quinazoline-2,4-diamine;

N²-(3,7-Dimethyl-octa-2,6-dienyl)-N⁴-(4-methoxy-phenyl)-N⁴-methyl-quinazoline-2,4-diamine;

-   N⁴-(4-Methoxy-phenyl)-N⁴-methyl-N²-(2-morpholin-4-yl-ethyl)-quinazoline-2,4-diamine;-   (4-Methoxy-phenyl)-methyl-(2-morpholin-4-yl-quinazolin-4-yl)-amine;

N²-(3,7-Dimethyl-octa-2,6-dienyl)-N⁴-(4-methyl-phenyl)-N⁴-methyl-quinazoline-2,4-diamine;

(2-Chloro-6,7-dimethoxyquinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;

(5,6,7,8-Tetrahydro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;

-   (2-Chloro-quinazolin-4-yl)-(4-methoxy-benzyl)-methyl-amine;-   (4-Methoxy-phenyl)-methyl-quinazolin-4-yl-amine;-   (4-Methyl-phenyl)-methyl-quinazolin-4-yl-amine;-   (2-Chloro-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl)-methyl-amine;-   (2-Chloro-quinazolin-4-yl)-isopropyl-(4-methoxy-phenyl)-amine;-   (2-Chloro-quinazolin-4-yl)-cyclohexyl-(4-methoxy-phenyl)-amine;-   (2-Chloro-quinazolin-4-yl)-(2,3-dimethoxy-phenyl)-methyl-amine;-   (2-Chloro-quinazolin-4-yl)-ethyl-(4-methoxy-phenyl)-amine;-   (2-Chloro-quinazolin-4-yl)-(2,4-dimethoxy-phenyl)-methyl-amine;-   (2-Chloro-quinazolin-4-yl)-(2,5-dimethoxy-phenyl)-methyl-amine;-   (2-Chloro-quinazolin-4-yl)-(3-methoxy-phenyl)-methyl-amine;-   (2-Chloro-quinazolin-4-yl)-(2-methoxy-phenyl)-methyl-amine;-   4-Chloro-benzoic acid    N′-methyl-N′-(2-methylthio-quinazolin-4-yl)-hydrazide;-   Benzoic acid N′-methyl-N′-(2-methylthio-quinazolin-4-yl)-hydrazide;-   Thiophene-2-carboxylic acid    N′-methyl-N′-(2-methylthio-quinazolin-4-yl)-hydrazide;

N²-[2-(1H-Imidazol-4-yl)-ethyl]-N⁴-(4-methoxy-phenyl)-N⁴-methyl-quinazoline-2,4-diamine;

N²-(3-Dimethylamino-propyl)-N⁴-(4-methoxy-phenyl)-N⁴-methyl-quinazoline-2,4-diamine;

N²-(2-Hydroxyethyl)-N⁴-(6-methoxypyridin-3-yl)-N⁴-methyl-quinazoline-2,4-diamine;

N⁴-(6-methoxypyridin-3-yl)-N⁴-methyl-quinazoline-2,4-diamine;

(2-Chloro-quinazolin-4-yl)-(4-methylcarboxyphenyl)-methyl-amine;

(2-methoxy-quinazolin-4-yl)-(4-methoxyphenyl)-methylamine;

(2-Chloro-quinazolin-4-yl)-(4-hydroxyphenyl)-methylamine;

(2-Fluoromethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;

-   (2-Chloro-6-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;

(2-Chloro-7-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;

(2-Chloro-5-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;

(2-Chloro-8-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;

(2,6-Dichloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;

(2,7-Dichloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;

(5-Chloro-2-isopropoxy-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;

(Isoquinolin-1-yl)-(4-methoxy-phenyl)-methyl-amine;

(4-Methoxy-phenyl)-methyl-(quinolin-4-yl)-amine;

(2-Chloro-quinazolin-4-yl)-(3,4-methylenedioxyphenyl)-methyl-amine;

(2-Chloro-quinazolin-4-yl)-(3,4-dimethoxy-phenyl)-methyl-amine;

(2-Chloro-quinazolin-4-yl)-(4-phenoxy-phenyl)-methyl-amine;

(2-Chloro-quinazolin-4-yl)-(4-propoxy-phenyl)-methyl-amine;

(4-Methoxy-phenyl)-methyl-(2-methyl-quinazolin-4-yl)-amine;

4-Methoxy-benzoic acidN′-methyl-N′-(2-trifluoromethyl-quinazolin-4-yl)-hydrazide;

3-Methyl-benzoic acidN′-methyl-N′-(2-methylthio-quinazolin-4-yl)-hydrazide;

4-Fluoro-benzoic acidN′-methyl-N′-(2-methylthio-quinazolin-4-yl)-hydrazide; and

2-Fluoro-benzoic acidN′-methyl-N′-(2-trifluoromethyl-quinazolin-4-yl)-hydrazide;

(2-Chloro-quinazolin-4-yl)-(2,5-dimethoxy-phenyl)-amine;

5-Chloro-N²,N⁴-bis-(4-methoxy-phenyl)-N²,N⁴-dimethyl-quinazoline-2,4-diamine;

(2-Chloromethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;

(2-Ethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;

(2-Hydroxymethyl-quinazolin-4-yl)-4-methoxy-phenyl)-methyl-amine;

(2-Dimethylaminomethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;

(4-Methoxy-phenyl)-(2-phenyl-quinazolin-4-yl)-methyl-amine;

(4-Difluoromethoxy-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;

(3-Fluoro-4-methoxy-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;

(4-Isopropoxy-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;

(4-Ethyl-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;

(2-Methyl-quinazolin-4-yl)-(2,4,6-trimethoxy-phenyl)-methyl-amine;

(2,8-Dichloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;

(2,5-Dichloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;

(5-Methoxy-2-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;

(4-Methoxy-phenyl)-(2-methyl-pyrido[2,3-d]pyrimidin-4-yl)-methyl-amine;

(4-Hydroxy-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;

(2-Chloro-quinazolin-4-yl)-(4-ethoxy-phenyl)-methylamine;

(2-Methyl-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl)-methyl-amine;

(2-Fluoro-4-methoxy-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;

(2-Methyl-quinazolin-4-yl)-(4-nitro-phenyl)-methyl-amine;

(4-Amino-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;

(4-Azido-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;

(4-Amino-2,6-dibromo-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;

(4-Amino-2-bromo-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;

(4-Dimethylamino-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;

(4-Ethoxy-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;

(4-Methoxy-phenyl-2,3,5,6-d₄)-(2-methyl-quinazolin-4-yl)-methyl-amine;

(4-Methoxy-phenyl)-(2-methyl-6-nitro-quinazolin-4-yl)-methyl-amine;

(6-Amino-2-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;

-   (6-Azido-2-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;-   (7-Amino-2-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;

(7-Azido-2-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;

-   Ethyl    4-(N-(4-Methoxy-phenyl)-N-methylamino)quinazoline-2-carboxylate;

Succinimidyl 4-(N-Methyl-N-(2-methylquinazolin-4-yl)amino)benzoic AcidEster;

(2-Methylthio-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;

(2-Azido-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;

(2-Dimethylamino-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;

(2-Methylamino-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;

(4-Fluoro-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;

(6-Methoxy-pyridazin-3-yl)-(2-methyl-quinazolin-4-yl)-methyl-amine;

(5-Methoxy-pyrazin-2-yl)-(2-methyl-quinazolin-4-yl)-methyl-amine;

(2-Dimethylamino-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl)-methyl-amine;

(2-Methylamino-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl)-methyl-amine;

(5-Methoxy-pyridin-2-yl)-(2-methyl-quinazolin-4-yl)-methyl-amine;

Difluoromethyl-(4-methoxy-phenyl)-(2-methyl-quinazolin-4-yl)-amine;

(4-Methoxy-phenyl)-(2-methyl-pteridin-4-yl)-methyl-amine;

(5-Methoxy-pyrimidin-2-yl)-(2-methyl-quinazolin-4-yl)-methyl-amine;

and pharmaceutically acceptable salts or solvates thereof.

The present invention also provides novel compounds, which are potenttubulin inhibitors, topoisomerase II inhibitors, caspase-3 activatorsand/or apoptosis inducers/promoters. Specifically, the novel compoundsof the present invention are represented by Formula IV andpharmaceutically acceptable salts or solvates thereof:

wherein

-   R₁ is methyl or ethyl, and preferably methyl;-   A ring is a carbocycle, aryl or heteroaryl;-   R₂-R₁₇ are independently H, halo, N₃, OH, thiol, nitro, CN, NH₂,    C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆    alkylthiol, halo-C₁₋₆ alkyl, C₂₋₆ alkenyl-O—, C₂₋₆ alkynyl-O—,    hydroxy-C₁₋₆ alkyl, C₁₋₆ alkoxy-C₁₋₆ alkyl, C₁₋₆ acyl, C₁₋₆ acyloxy,    —C₁₋₆ alkyl-C(O)O—C₁₋₆ alkyl, —C(O)O—C₁₋₆ alkyl, C₁₋₆    alkyl-C(O)O—C₁₋₆ alkyl-, C₁₋₆ acylamido, —N(R^(a))(R^(b)), —C₁₋₆    alkyl-C(O)N(R^(a))(R^(b)), —C(O)N(R^(a))(R^(b)),    N(R^(a))(R^(b))—C₁₋₆ alkyl-, 3, 4, 5, or 6-membered carbocycle,    heterocycle, aryl, or heteroaryl, wherein R^(a) and R^(b) are    independently H, OH (R^(a) and R^(b) are not both OH), C₂₋₆    hydroxyalkyl, or C₁₋₆ alkyl, or R^(a) and R^(b) together with the    nitrogen atom to which they are both linked form a 3, 4, 5 or    6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and    morpholinyl); wherein any of the groups is optionally substituted    with 1-3 substituents wherein each substituent is independently    halo, N₃, OH, thiol, nitro, CN, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆    alkynyl, C₁₋₆ alkoxy, C₁₋₆ alkylthiol, C₂₋₆ alkenyl-O—, C₂₋₆    alkynyl-O—, hydroxy-C₁₋₆ alkyl, C₁₋₆ alkoxy-C₁₋₆ alkyl, C₁₋₆ acyl,    C₁₋₆ acyloxy, —C₁₋₆ alkyl-C(O)O—C₁₋₆ alkyl, —C(O)O—C₁₋₆ alkyl, C₁₋₆    alkyl-C(O)O—C₁₋₆ alkyl-, C₁₋₆ acylamido, —N(R^(a))(R^(b)), —C₁₋₆    alkyl-C(O)N(R^(a))(R^(b)), —C(O)N(R^(a))(R^(b)),    N(R^(a))(R^(b))—C₁₋₆ alkyl-, wherein R^(a) and R^(b) are    independently H, OH (R^(a) and R^(b) are not both OH), C₂₋₆    hydroxyalkyl, or C₁₋₆ alkyl or R^(a) and R^(b) together with the    nitrogen atom to which they are both linked form a 3, 4, 5 or    6-membered heterocycle, wherein optionally any two adjacent R₇-R₁₁    groups together form a 3, 4, 5 or 6-membered carbocycle or    heterocycle, with the proviso that when A ring is aryl or    heteroaryl, then there are no substituents R₁₄-R₁₇; and with the    proviso that when A ring is aryl or heteroaryl and U is C, then R₅    is H or F, preferably H; and-   B, D, Q, T, U, V, W, X, Y and Z are independently C or N, wherein at    least one of B and D is N; wherein when B, D, W, X, Y or Z is N,    then there is no substituent at the N; and wherein when A is    heteroaryl and Q, T, U or V is N, then there is no sub stituent at    the N; and-   wherein when A is carbocycle and W, X, Y and Z are all carbon atoms,    then the compound is not    2-amino-4-(N-ethylanilino)-5,6,7,8-tetrahydro-quinazoline; and-   wherein when A is benzo and W, X, Y and Z are all C, then (1) R₉ is    not (C₁₋₃ alkyl)OC(O)alkoxy-; and (2) when R₉ is H, then at least    one of R₈ and R₁₀ are not H or C₁₋₆ alkyl, or halo; and-   wherein when A is heteroaryl and W, X, Y and Z are all C, when R₉ is    H, then at least one of R₈ and R₁₀ is not H or alkyl, provided that    R₈ and R₁₀ may be both alkyl.

Preferably when R₉ is H then R₈ or R₁₀ or both are independentlyselected from the group OH; N₃; —XR_(2a) wherein X is S or O and R_(2a)is C₁₋₆ alkyl (preferably C₁₋₃ alkyl, more preferably CH₃) optionallysubstituted with OH or halo; —NH(R_(2b)) or N(R_(2b))(R_(2c)) whereinR_(2b) and R_(2c) are independently C₁₋₆ alkyl (preferably C₁₋₃ alkyl,more preferably CH₃) optionally substituted with OH or halo (preferablyF, and wherein optionally R_(2b) and R_(2c) may together form a 3-6membered heterocycle; and —C(O)OR_(2d) wherein R_(2d) is C₁₋₆ alkyl(preferably C₁₋₃ alkyl); and more preferably R₉ is not H.

In some embodiments of the compounds of Formula IV, one of W, X, Y and Zis N. In other embodiments of the compounds of Formula IV, two of W, X,Y and Z are N. In any of the embodiments, preferably one or two of Q, T,U and V are N. In preferred embodiments, B and D both are N.

One group of the compounds of the present invention are represented byFormula IVa:

or a pharmaceutically acceptable salt or solvate thereof, wherein:

-   R₁ is methyl, ethyl, preferably methyl;-   R₂-R₁₇ are independently H, halo, N₃, OH, thiol, nitro, CN, NH₂,    C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆    alkylthiol, halo-C₁₋₆ alkyl, C₂₋₆ alkenyl-O—, C₂₋₆ alkynyl-O—,    hydroxy-C₁₋₆ alkyl, C₁₋₆ alkoxy-C₁₋₆ alkyl, C₁₋₆ acyl, C₁₋₆ acyloxy,    —C₁₋₆ alkyl-C(O)O—C₁₋₆ alkyl, —C(O)O—C₁₋₆ alkyl, C₁₋₆    alkyl-C(O)O—C₁₋₆ alkyl-, C₁₋₆ acylamido, —N(R^(a))(R^(b)), —C₁₋₆    alkyl-C(O)N(R^(a))(R^(b)), —C(O)N(R^(a))(R^(b)),    N(R^(a))(R^(b))—C₁₋₆ alkyl-, 3, 4, 5, or 6-membered carbocycle,    heterocycle, aryl, or heteroaryl, wherein R^(a) and R^(b) are    independently H, OH (R^(a) and R^(b) are not both OH), C₂₋₆    hydroxyalkyl, or C₁₋₆ alkyl, or R^(a) and R^(b) together with the    nitrogen atom to which they are both linked form a 3, 4, 5 or    6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and    morpholinyl); wherein any of the groups is optionally substituted    with 1-3 substituents wherein each substituent is independently    halo, N₃, OH, thiol, nitro, CN, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆    alkynyl, C₁₋₆ alkoxy, C₁₋₆ alkylthiol, C₂₋₆ alkenyl-O—, C₂₋₆    alkynyl-O—, hydroxy-C₁₋₆ alkyl, C₁₋₆ alkoxy-C₁₋₆ alkyl, C₁₋₆ acyl,    C₁₋₆ acyloxy, —C₁₋₆ alkyl-C(O)O—C₁₋₆ alkyl, —C(O)O—C₁₋₆ alkyl, C₁₋₆    alkyl-C(O)O—C₁₋₆ alkyl-, C₁₋₆ acylamido, —N(R^(a))(R^(b)), —C₁₋₆    alkyl-C(O)N(R^(a))(R^(b)), —C(O)N(R^(a))(R^(b)),    N(R^(a))(R^(b))—C₁₋₆ alkyl-, wherein R^(a) and R^(b) are    independently H, OH (R^(a) and R^(b) are not both OH), C₂₋₆    hydroxyalkyl, or C₁₋₆ alkyl or R^(a) and R^(b) together with the    nitrogen atom to which they are both linked form a 3, 4, 5 or    6-membered heterocycle, wherein optionally any two adjacent R₇-R₁₁    groups together form a 3, 4, 5 or 6-membered carbocycle or    heterocycle; and-   B, D, W, X, Y, and Z are independently C or N, provided that at    least one of B and D is N, at least one of W, X, Y, and Z is N, and    when B, D, W, X, Y, or Z is N then there is no substituent at the N.

In some embodiments, one of X, Y, W and Z is N. In other embodiments,two of X, Y, W and Z are N. Preferably D is nitrogen, and morepreferably both B and D are N.

In a preferred embodiment, compounds of the present invention haveFormula IVa, or a pharmaceutically acceptable salt or solvate thereof,wherein:

-   R₁ is methyl or ethyl, preferably methyl;-   R₂ is a member of the group consisting of H, halo, N₃, C₁₋₄ alkoxy,    C₁₋₄ alkylthiol, hydroxyC₁₋₄ alkyl, C₁₋₄ alkyl, and —N(R^(a))(R^(b))    wherein R^(a) and R^(b) are independently H, OH (R^(a) and R^(b) are    not both OH), C₂₋₄ hydroxyalkyl, or C₁₋₄ alkyl or R^(a) and R^(b)    together with the nitrogen atom to which they are both linked form a    3, 4, 5 or 6-membered heterocycle; each of the member being    optionally substituted by 1-4 substituents wherein each substituent    is independently halo, OH, or C₁₋₄ alkyl;-   R₇ and R₁₁ are independently H, halo (preferably F), CH₃, or OCH₃;-   R₈ and R₁₀ are independently H, halo (preferably F or Cl), C₁₋₃    alkyl (preferably CH₃) optionally substituted with halo (preferably    1-3 F), C₁₋₃ alkoxy (preferably OCH₃), or C₁₋₃ alkylthiol    (preferably —S—CH₃);-   R₉ is H, OH, Cl, N₃, C₁₋₄ alkoxy, C₁₋₄ alkylthiol, hydroxyC₁₋₄    alkyl, C₁₋₄ alkyl, —COOR^(c) wherein R^(c) is C₁₋₃ alkyl, or    —N(R^(a))(R^(b)) wherein R^(a) and R^(b) are independently H, OH    (R^(a) and R^(b) are not both OH), C₂₋₄ hydroxyalkyl, or C₁₋₄ alkyl    or R^(a) and R^(b) together with the nitrogen atom to which they are    both linked form a 3, 4, 5 or 6-membered heterocycle; each of the    member being optionally substituted by 1-4 substituents wherein each    substituent is independently halo, OH, or C₁₋₄ alkyl; and optionally    two adjacent R₈, R₉, and R₁₀ groups may together form a 3, 4, 5, or    6-membered carbocycle, heterocycle, preferably heterocyle; and-   B, D, W, X, Y, and Z are independently C or N, and at least one of B    and D is N, at least one of W, X, Y and Z is N, and when B, D, W, X,    Y, or Z is N then there is no sub stituent at the N. Preferably D    is N. In some embodiments, both B and D are N.

In specific embodiments, only one of W, X, Y and Z is N. In otherspecific embodiments, two of W, X, Y and Z are N.

In preferred embodiments of the compound of Formula IVa, R₉ is selectedfrom the group:

—OR_(9a), wherein R_(9a) is methyl, ethyl, fluoromethyl (CH₂F, CHF₂,CF₃), or fluoroethyl;

—N₃;

—N(CH₃)₂;

—NHCH₃; and

—COOR_(9b), wherein R_(9b) is H or C₁₋₂ alkyl.

Another group of compounds of the present invention are represented byFormula IVb:

or pharmaceutically acceptable salts or solvates thereof, wherein:

-   R₂-R₁₇ are independently H, halo, N₃, OH, thiol, nitro, CN, NH₂,    C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆    alkylthiol, halo-C₁₋₆ alkyl, C₂₋₆ alkenyl-O—, C₂₋₆ alkynyl-O—,    hydroxy-C₁₋₆ alkyl, C₁₋₆ alkoxy-C₁₋₆ alkyl, C₁₋₆ acyl, C₁₋₆ acyloxy,    —C₁₋₆ alkyl-C(O)O—C₁₋₆ alkyl, —C(O)O—C₁₋₆ alkyl, C₁₋₆    alkyl-C(O)O—C₁₋₆ alkyl-, C₁₋₆ acylamido, —N(R^(a))(R^(b)), —C₁₋₆    alkyl-C(O)N(R^(a))(R^(b)), —C(O)N(R^(a))(R^(b)),    N(R^(a))(R^(b))—C₁₋₆ alkyl, 3, 4, 5, or 6-membered carbocycle,    heterocycle, aryl, or heteroaryl, wherein R^(a) and R^(b) are    independently H, OH (R^(a) and R^(b) are not both OH), C₂₋₆    hydroxyalkyl, or C₁₋₆ alkyl, or R^(a) and R^(b) together with the    nitrogen atom to which they are both linked form a 3, 4, 5 or    6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and    morpholinyl); wherein any of the groups is optionally substituted    with 1-3 substituents wherein each substituent is independently    halo, N₃, OH, thiol, nitro, CN, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆    alkynyl, C₁₋₆ alkoxy, C₁₋₆ alkylthiol, C₂₋₆ alkenyl-O—, C₂₋₆    alkynyl-O—, hydroxy-C₁₋₆ alkyl, C₁₋₆ alkoxy-C₁₋₆ alkyl, C₁₋₆ acyl,    C₁₋₆ acyloxy, —C₁₋₆ alkyl-C(O)O—C₁₋₆ alkyl, —C(O)O—C₁₋₆ alkyl, C₁₋₆    alkyl-C(O)O—C₁₋₆ alkyl-, C₁₋₆ acylamido, —N(R^(a))(R^(b)), —C₁₋₆    alkyl-C(O)N(R^(a))(R^(b)), —C(O)N(R^(a))(R^(b)),    N(R^(a))(R^(b))—C₁₋₆ alkyl-, wherein R^(a) and R^(b) are    independently H, OH (R^(a) and R^(b) are not both OH), C₂₋₆    hydroxyalkyl, or C₁₋₆ alkyl or R^(a) and R^(b) together with the    nitrogen atom to which they are both linked form a 3, 4, 5 or    6-membered heterocycle, wherein optionally any two adjacent R₇-R₁₁    groups together form a 3, 4, 5 or 6-membered carbocycle or    heterocycle; and-   B and D are independently C or N, provided that at least one of B    and D is N, and when B or D is N then there is no substituent at the    N; with the proviso that said compound is not    2-amino-4-(N-ethylanilino)-5,6,7,8-tetrahydro-quinazoline.

Preferably, in the compounds of Formula IVb, D is N, and more preferablyboth B and D are N.

In preferred embodiments, when R₁ is ethyl then at least one of R₈, R₉,and R₁₀ is not H; preferably R₉ is not H. Also preferably, when R₉ is Hthen R₈ or R₁₀ or both are independently selected from the group OH; N₃;amido; N-dimethylamido; —XR_(9a) wherein X is S or O and R_(9a) is C₁₋₆alkyl (preferably C₁₋₃ alkyl, more preferably CH₃) optionallysubstituted with OH or halo; C₁₋₃ alkyl optionally substituted with halo(preferably F); —N(R^(a))(R^(b)) wherein R^(a) and R^(b) areindependently H, OH (R^(a) and R^(b) are not both OH), or C₁₋₆ alkyl(preferably C₁₋₃ alkyl, more preferably CH₃) optionally substituted withOH or halo (preferably F, and wherein optionally R_(2b) and R_(2c) maytogether form a 3-6 membered heterocycle; and —C(O)OR^(c) wherein R^(c)is C₁₋₆ alkyl (preferably C₁₋₃ alkyl).

In a preferred embodiment of the compound of Formula IVb:

-   R₁ is methyl or ethyl, preferably methyl;-   R₃-R₆, R₁₂-R₁₇ are as defined above;-   R₂ is a member of the group consisting of H, halo, N₃, C₁₋₄ alkoxy,    C₁₋₄ alkylthiol, hydroxyC₁₋₄ alkyl, C₁₋₄ alkyl, and —N(R^(a))(R^(b))    wherein R^(a) and R^(b) are independently H, OH (R^(a) and R^(b) are    not both OH), C₂₋₄ hydroxyalkyl, or C₁₋₄ alkyl or R^(a) and R^(b)    together with the nitrogen atom to which they are both linked form a    3, 4, 5 or 6-membered heterocycle; each of the member being    optionally substituted by 1-4 substituents wherein each substituent    is independently halo, OH, or C₁₋₄ alkyl;-   R₇ and R₁₁ are independently H, halo (preferably F), CH₃, or OCH₃;-   R₈ and R₁₀ are independently H, halo (preferably F or Cl), C₁₋₃    alkyl (preferably CH₃) optionally substituted with halo (preferably    1-3 F), C₁₋₃ alkoxy (preferably OCH₃), or C₁₋₃ alkylthiol    (preferably —S—CH₃);-   R₉ is OH, Cl, N₃, C₁₋₄ alkoxy, C₁₋₄ alkylthiol, hydroxyC₁₋₄ alkyl,    C₁₋₄ alkyl, —COOR^(c) wherein R^(c) is C₁₋₃ alkyl, or    —N(R^(a))(R^(b)) wherein R^(a) and R^(b) are independently H, OH    (R^(a) and R^(b) are not both OH), C₂₋₄ hydroxyalkyl, or C₁₋₄ alkyl    or R^(a) and R^(b) together with the nitrogen atom to which they are    both linked form a 3, 4, 5 or 6-membered heterocycle; each of the    member being optionally substituted by 1-4 substituents wherein each    substituent is independently halo, OH, or C₁₋₄ alkyl; and optionally    two adjacent R₈, R₉, and R₁₀ groups may together form a 3, 4, 5, or    6-membered carbocycle, heterocycle, preferably heterocyle; and-   B and D are independently C or N, and at least one of B and D is N.

In more preferred embodiments of the compound of Formula IVa, R₉ isselected from the group:

—OR_(9a), wherein R_(9a) is methyl, ethyl, fluoromethyl (e.g., CH₂F,CHF₂, CF₃), fluoroethyl;

—N₃;

—N(CH₃)₂;

—NHCH₃; and

—COOR_(9b), wherein R_(9b) is H or C₁₋₂ alkyl.

Other novel compounds of the present invention are those represented byFormula V:

or a pharmaceutically acceptable salt or solvate thereof, wherein:

-   R₁ is methyl or ethyl, preferably methyl;-   R₅ is H, F, Cl, N₃, methyl, methoxy or NH₂, with the proviso that    when R₅ is methoxy, R₁ is methyl; Preferably R₅ is H, F or N₃, more    preferably H or F, and most preferably H;-   R₂-R₄, and R₆-R₁₃ are independently H, halo, N₃, OH, thiol, nitro,    CN, NH₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆    alkylthiol, halo-C₁₋₆ alkyl, C₂₋₆ alkenyl-O—, C₂₋₆ alkynyl-O—,    hydroxy-C₁₋₆ alkyl, C₁₋₆ alkoxy-C₁₋₆ alkyl, C₁₋₆ acyl, C₁₋₆ acyloxy,    —C₁₋₆ alkyl-C(O)O—C₁₋₆ alkyl, —C(O)O—C₁₋₆ alkyl, C₁₋₆    alkyl-C(O)O—C₁₋₆ alkyl-, C₁₋₆ acylamido, —N(R^(a))(R^(b)), —C₁₋₆    alkyl-C(O)N(R^(a))(R^(b)), —C(O)N(R^(a))(R^(b)),    N(R^(a))(R^(b))—C₁₋₆ alkyl-, 3, 4, 5, or 6-membered carbocycle,    heterocycle, aryl, or heteroaryl, wherein R^(a) and R^(b) are    independently H, OH (R^(a) and R^(b) are not both OH), C₂₋₆    hydroxyalkyl, or C₁₋₆ alkyl, or R^(a) and R^(b) together with the    nitrogen atom to which they are both linked form a 3, 4, 5 or    6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and    morpholinyl); wherein any of the groups is optionally substituted    with 1-3 substituents wherein each substituent is independently    halo, N₃, OH, thiol, nitro, CN, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆    alkynyl, C₁₋₆ alkoxy, C₁₋₆ alkylthiol, C₂₋₆ alkenyl-O—, C₂₋₆    alkynyl-O—, hydroxy-C₁₋₆ alkyl, C₁₋₆ alkoxy-C₁₋₆ alkyl, C₁₋₆ acyl,    C₁₋₆ acyloxy, —C₁₋₆ alkyl-C(O)O—C₁₋₆ alkyl, —C(O)O—C₁₋₆ alkyl, C₁₋₆    alkyl-C(O)O—C₁₋₆ alkyl-, C₁₋₆ acylamido, —N(R^(a))(R^(b)), —C₁₋₆    alkyl-C(O)N(R^(a))(R^(b)), —C(O)N(R^(a))(R^(b)),    N(R^(a))(R^(b))—C₁₋₆ alkyl-, wherein R^(a) and R^(b) are    independently H, OH (R^(a) and R^(b) are not both OH), C₂₋₆    hydroxyalkyl, or C₁₋₆ alkyl or R^(a) and R^(b) together with the    nitrogen atom to which they are both linked form a 3, 4, 5 or    6-membered heterocycle, wherein optionally any two adjacent R₇-R₁₁    groups together form a 3, 4, 5 or 6-membered carbocycle or    heterocycle; and-   B, D, Q, T, U, V, W, X, Y and Z are independently C or N, provided    that at least one of B and D is N, and at least one of W, X, Y and Z    is N, and wherein when B, D, Q, T, U, V, W, X, Y or Z is N, then    there is no substituent at the N.

In a specific embodiment, preferably when R₉ is H, at least one of R₈and R₁₀ is not H, more preferably R₉ is other than H.

In some specific embodiments, B is C and D is N. In other specificembodiments, B is N and D is C. In preferred embodiments, both B and Dare N.

In one embodiment of the compounds of Formula V,

-   R₂ is H; halo; N₃;-   C₁₋₆ alkyl (preferably C₁₋₃ alkyl, more preferably CH₃) optionally    substituted with OH or halo (preferably F, e.g., monofluoro,    difluoro, or trifluoro);-   —XR_(2a) wherein X is S or O, and R_(2a) is C₁₋₆ alkyl (preferably    C₁₋₃ alkyl, more preferably CH₃) optionally substituted with OH or    halo (preferably F, e.g., monofluoro-, difluoro-, or    trifluoro-substituted);-   —CO₂R^(d), wherein R^(d) is C₁₋₃ alkyl, preferably methyl or ethyl;    or

—N(R^(a))(R^(b)) wherein R^(a) and R^(b) are independently H, OH (R^(a)and R^(b) are not both OH), C₁₋₃ alkyl (preferably CH₃), C₁₋₆hydroxyalkyl (preferably C₂₋₃ hydroxyalkyl, more preferably —CH₂CH₂OH),or C₁₋₆ alkyl (preferably C₁₋₃ alkyl, more preferably CH₃) that isoptionally substituted with —N(R^(e))(R^(f)) wherein R^(e) and R^(f) areindependently H, OH (R^(e) and R^(f) are not both OH), C₁₋₃ alkyl(preferably CH₃), or C₂₋₃ hydroxyalkyl (preferably —CH₂CH2OH), andwherein optionally R^(a) and R^(b) together may form a 3, 4, 5 or6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, andmorpholinyl).

In another embodiment of the compound of Formula V, R₂ is H, methyl,ethyl, Cl, F, fluoromethyl (CH₂F, CHF₂, CF₃), C₁₋₃ hydroxyalkyl(preferably CH₂OH or CH₂CH₂OH), NH₂, NH₂OH, —NHCH₂CH₂OH, NHCH₃, N(CH₃)₂,N₃, morpholino, OCH₃, OC₂H₅, or SCH₃.

In preferred embodiment, R₂ is H, methyl, Cl, —CH₂OH, —NH₂, —NHCH₃,—NHCH₂CH₂OH, —OCH₃, —SCH₃, or —CH₂F.

In one embodiment, R₉ is selected from the group consisting of H; OH;Cl; N₃; C₁₋₃ alkyl (preferably methyl or ethyl) or C₁₋₃ haloalkyl(preferably monofluoromethyl, difluoromethyl, trifluoromethyl);—OR_(9a), wherein R_(9a) is C₁₋₃ alkyl (i.e., methyl, ethyl, propyl,isopropyl) or C₁₋₃ haloalkyl (e.g., fluoroalkyl, preferablyfluoromethyl, i.e., CH₂F, CHF₂, CF₃); —N(R^(a))(R^(b)) wherein R^(a) andR^(b) are independently H or C₁₋₃ alkyl; or —COOR_(9b), wherein R_(9b)is C₁₋₃ alkyl (preferably methyl or ethyl); and optionally R₉ and one ofR₈ and R₁₀ together form a 3, 4, 5, or 6-membered heterocycle.

In another embodiment, R₉ is —OCH₃, —OC₂H₅, —N(CH₃)₂, —CO₂CH₃, —OCHF₂,or N₃.

In yet another embodiment, when R₉ is H, at least one of R₈ and R₁₀ isnot H. In another embodiment, when R₉ is alkyl, R₂ is not H.

In a specific embodiment, compounds of the invention include compoundsof Formula V or pharmaceutically acceptable salts or solvates thereof,wherein:

-   R₁ is C₁₋₂ alkyl, and preferably R₁ is methyl;-   R₅ is H or F, preferably H;-   R₂-R₄, R₆, R₈-R₁₀, R₁₂ and R₁₃ are independently H; halo; N₃;    -   C₁₋₆ alkyl (preferably C₁₋₃ alkyl, more preferably CH₃)        optionally substituted with 1, 2 or 3 substituents, each        substituent being independently OH, halo, C₁₋₃ alkoxy, (halo)        C₁₋₃ alkoxy, —N(R^(a))(R^(b)) where R^(a) and R^(b) are        independently H, OH (R^(a) and R^(b) are not both OH), C₂₋₆        hydroxyalkyl, or C₁₋₆ alkyl or R^(a) and R^(b) together with the        nitrogen atom to which they are both linked form a 3, 4, 5 or        6-membered heterocycle;    -   —XR^(c) wherein X is S or O and R^(c) is C₁₋₆ alkyl (preferably        C₁₋₃ alkyl, more preferably CH₃) optionally substituted with        with 1, 2 or 3 substituents, each substituent being        independently OH, halo, C₁₋₃ alkoxy, C₂-C₄ alkenyl, C₂-C₄        alkynyl, —N(R^(a))(R^(b)) where R^(a) and R^(b) are        independently H, OH (R^(a) and R^(b) are not both OH), C₂₋₆        hydroxyalkyl, or C₁₋₆ alkyl or R^(a) and R^(b) together with the        nitrogen atom to which they are both linked form a 3, 4, 5 or        6-membered heterocycle;    -   —(C₀₋₃ alkyl)CO₂R^(d), wherein R^(d) is an C₁₋₆ alkyl        (preferably C₁₋₃ alkyl, more preferably methyl or ethyl)        optionally substituted with 1, 2 or 3 substituents, each        substituent being independently OH, halo, C₁₋₃ alkoxy (e.g.,        fluoroalkoxy), —N(R^(a))(R^(b)) where R^(a) and R^(b) are        independently H, OH (R^(a) and R^(b) are not both OH), C₂₋₆        hydroxyalkyl, or C₁₋₆ alkyl or R^(a) and R^(b) together with the        nitrogen atom to which they are both linked form a 3, 4, 5 or        6-membered heterocycle; or    -   —N(R^(a))(R^(b)) where R^(a) and R^(b) are independently H; OH        (R^(a) and R^(b) are not both OH); C₂₋₆ hydroxyalkyl; C₁₋₆        alkyl; or C₁₋₆ alkyl substituted with —N(R^(e))(R^(f)) where        R^(e) and R^(f) are independently H, OH (R^(e) and R^(f) are not        both OH), or C₁₋₃ alkyl; wherein optionally R^(a) and R^(b)        together, and/or R^(e) and R^(f) together, with the nitrogen        atom to which they are linked form a 3, 4, 5 or 6-membered        heterocycle; preferably when R₉ is H, at least one of R₈ and R₁₀        is not H, more preferably R₉ is other than H.-   R₇ and R₁₁ are independently H, halo (preferably F or Cl, more    preferably F), C₁₋₃ alkyl (preferably CH₃), or C₁₋₄ alkoxy    (preferably OCH3); and-   B, D, Q, T, U, V, W, X, Y, and Z are as defined above, provided that    when B, D, Q, T, U, V, W, X, Y or Z is N there is no substituent at    the N.

In another preferred embodiment of the compounds of Formula V,

-   R₁ is methyl or ethyl, more preferably methyl;-   R₂ is H; halo; N₃;-   C₁₋₆ alkyl (preferably C₁₋₃ alkyl, more preferably CH₃) optionally    substituted with OH or halo (preferably F, e.g., monofluoro,    difluoro, or trifluoro);-   —XR_(2a) wherein X is S or O, and R_(2a) is C₁₋₆ alkyl (preferably    C₁₋₃ alkyl, more preferably CH₃) optionally substituted with OH or    halo (preferably F, e.g., monofluoro-, difluoro-, or    trifluoro-substituted);-   —CO₂R^(d), wherein R^(d) is C₁₋₃ alkyl, preferably methyl or ethyl;    or

—N(R^(a))(R^(b)) wherein R^(a) and R^(b) are independently H, OH (R^(a)and R^(b) are not both OH), C₁₋₃ alkyl (preferably CH₃), C₁₋₆hydroxyalkyl (preferably C₂₋₃ hydroxyalkyl, more preferably —CH₂CH₂OH),or C₁₋₆ alkyl (preferably C₁₋₃ alkyl, more preferably CH₃) that isoptionally substituted with —N(R^(e))(R^(f)) wherein R^(e) and R^(f) areindependently H, OH (R^(e) and R^(f) are not both OH), C₁₋₃ alkyl(preferably CH₃), or C₂₋₃ hydroxyalkyl (preferably —CH₂CH2OH), andwherein optionally R^(a) and R^(b) with N together may form a 3, 4, 5 or6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, andmorpholinyl);

-   R₃ and R₁₂ are independently H; halo; C₁₋₃ alkyl; or C₁₋₃ alkoxy;-   R₄, R₆, and R₁₃ are independently H; halo (preferably F or Cl); N₃;    C₁₋₃ alkyl (preferably CH₃); C₁₋₃ alkoxy (preferably OCH₃); or    —N(R^(a))(R^(b)) wherein R^(a) and R^(b) are independently H, OH,    C₁₋₃ alkyl, (hydroxy)C₁₋₃ alkyl, and optionally R^(a) and R^(b)    together may form a 3, 4, 5 or 6-membered heterocycle (e.g.,    piperidinyl, pyrrolidinyl, and morpholinyl), and wherein R^(a) and    R^(b) are not both OH;-   R₅ is H;-   R₇ and R₁₁ are independently H, halo (preferably F), CH₃, or OCH₃;-   R₈ and R₁₀ are independently H; halo (preferably F or Cl, more    preferably F); C₁₋₃ alkyl (preferably CH₃); C₁₋₃ alkoxy (preferably    OCH₃); and-   R₉ is selected from the group: H; OH; Cl; N₃; C₁₋₃ alkyl (preferably    methyl or ethyl) or C₁₋₃ haloalkyl (preferably monofluoromethyl,    difluoromethyl, trifluoromethyl); —OR_(9a), wherein R_(9a) is C₁₋₃    alkyl (i.e., methyl, ethyl, propyl, isopropyl) or C₁₋₃ haloalkyl    (e.g., fluoroalkyl, preferably fluoromethyl, i.e., CH₂F, CHF₂, CF₃);    —N(R^(a))(R^(b)) wherein R^(a) and R^(b) are independently H or C₁₋₃    alkyl; or —COOR_(9b), wherein R_(9b) is C₁₋₃ alkyl (preferably    methyl or ethyl); and optionally R₉ and one of R₈ and R₁₀ together    form a 3, 4, 5, or 6-membered heterocycle; preferably when R₉ is H,    at least one of R₈ and R₁₀ is not H, more preferably R₉ is other    than H; and-   B, D, Q, T, U, V, W, X, Y, and Z are independently C or N, provided    that at least one of B and D is N, and at least one of W, X, Y, and    Z is N, wherein when B, D, Q, T, U, V, W, X, Y, or Z is nitrogen,    then there is no substituent at the N.

In more preferred embodiment, compounds of the invention includecompounds of Formula V or pharmaceutically acceptable salts or solvatesthereof, wherein:

-   R₁ is methyl or ethyl, preferably methyl;-   R₂ is H, methyl, ethyl, Cl, F, fluoromethyl (CH₂F, CHF₂, CF₃), C₁₋₃    hydroxyalkyl (preferably CH₂OH or CH₂CH₂OH), NH₂, NH₂OH,    —NHCH₂CH₂OH, NHCH₃, N(CH₃)₂, N₃, morpholino, OCH₃, OC₂H₅, or SCH₃;-   R₃ and R₁₂ are independently H, CH₃, OCH₃, F, or Cl;-   R₄, R₆, and R₁₃ are independently H, CH₃, NH₂, N₃, F, or Cl;-   R₅ is H;-   R₇ and R₁₁ are independently H, F, or OCH₃;-   R₈ and R₁₀ are independently H, F, Cl, or OCH₃;-   R₉ is selected from the group of consisting of H; OH; Cl; N₃; C₁₋₃    alkyl (preferably methyl or ethyl); C₁₋₃ haloalkyl (preferably    monofluoromethyl, difluoromethyl, trifluoromethyl); —OR_(9a) where    R_(9a) is C₁₋₃ alkyl (i.e., methyl, ethyl, propyl, isopropyl) or    C₁₋₃ haloalkyl (e.g., fluoroalkyl, preferably fluoromethyl, i.e.,    CH₂F, CHF₂, CF₃); —N(R^(a))(R^(b)) wherein R^(a) and R^(b) are    independently H or C₁₋₃ alkyl; and —COOR_(9b), wherein R_(9b) is    C₁₋₃ alkyl (preferably methyl or ethyl), and optionally R₉ and one    of R₈ and R₁₀ together form a 3, 4, 5, or 6-membered heterocycle;    preferably when R₉ is H, at least one of R₈ and R₁₀ is not H, more    preferably R₉ is other than H; and-   B, D, Q, T, U, V, W, X, Y and Z are as defined above, provided that    when B, D, Q, T, U, V, W, X, Y or Z is N, then there is no    substituent at the N. Preferably in this embodiment, when R₉ is    alkyl, R₂ not H.

In a even more preferred embodiment, compounds of the invention includecompounds of Formula V or pharmaceutically acceptable salts or solvatesthereof, wherein R₁ is methyl; R₂ is H, methyl, Cl, —CH₂OH, —NH₂,—NHCH₃, —NHCH₂CH₂OH, —OCH₃, —SCH₃, or —CH₂F; R₃ and R₁₂ areindependently H, methyl, —OCH₃, or Cl; R₄ is H, methyl, or NH₂; R₅ is H;R₆ and R₁₃ are independently H or methyl; R₇ and R₁₁ are independently Hor F; R₈ and R₁₀ are independently H, or F or OCH₃; and R₉ is —OCH₃,—OC₂H₅, —N(CH₃)₂, —CO₂CH₃, —OCHF₂, or N₃; and B, D, Q, T, U, V, W, X, Y,and Z are as defined above, provided that when B, D, Q, T, U, V, W, X,Y, or Z is N, then there is no substituent at the N.

In all embodiments of the compounds of Formula V, it is preferred thatone of W, X, Y and Z is N, or two of W, X, Y and Z are N. In any of theembodiments, preferably one or two of Q, T, U and V are N. For example,Q and V can be both N and T and U are C.

Other preferred compounds of the present invention are those representedby Formula V, with the proviso that Q, T, U, and V are all carbon.Specifically, such compounds are represented by Formula Va:

or pharmaceutically acceptable salts or solvates thereof, wherein:

-   R₁ is methyl or ethyl, preferably methyl;-   R₅ is H, F, Cl, N₃, methyl, methoxy or NH₂, with the proviso that    when R₅ is methoxy, R₁ is methyl; Preferably R₅ is H, F or N₃, more    preferably H or F, and most preferably H;-   R₂-R₄, and R₆-R₁₃ are independently H, halo, N₃, OH, thiol, nitro,    CN, NH₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆    alkylthiol, halo-C₁₋₆ alkyl, C₂₋₆ alkenyl-O—, C₂₋₆ alkynyl-O—,    hydroxy-C₁₋₆ alkyl, C₁₋₆ alkoxy-C₁₋₆ alkyl, C₁₋₆ acyl, C₁₋₆ acyloxy,    —C₁₋₆ alkyl-C(O)O—C₁₋₆ alkyl, —C(O)O—C₁₋₆ alkyl, C₁₋₆    alkyl-C(O)O—C₁₋₆ alkyl-, C₁₋₆ acylamido, —N(R^(a))(R^(b)), —C₁₋₆    alkyl-C(O)N(R^(a))(R^(b)), —C(O)N(R^(a))(R^(b)), N(R^(a))R^(b))—C₁₋₆    alkyl-, 3, 4, 5, or 6-membered carbocycle, heterocycle, aryl, or    heteroaryl, wherein R^(a) and R^(b) are independently H, OH (R^(a)    and R^(b) are not both OH), C₂₋₆ hydroxyalkyl, or C₁₋₆ alkyl, or    R^(a) and R^(b) together with the nitrogen atom to which they are    both linked form a 3, 4, 5 or 6-membered heterocycle (e.g.,    piperidinyl, pyrrolidinyl, and morpholinyl); wherein any of the    groups is optionally substituted with 1-3 substituents wherein each    substituent is independently halo, N₃, OH, thiol, nitro, CN, C₁₋₆    alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ alkylthiol,    C₂₋₆ alkenyl-O—, C₂₋₆ alkynyl-O—, hydroxy-C₁₋₆ alkyl, C₁₋₆    alkoxy-C₁₋₆ alkyl, C₁₋₆ acyl, C₁₋₆ acyloxy, —C₁₋₆ alkyl-C(O)O—C₁₋₆    alkyl, —C(O)O—C₁₋₆ alkyl, C₁₋₆ alkyl-C(O)O—C₁₋₆ alkyl-, C₁₋₆    acylamido, —N(R^(a))(R^(b)), —C₁₋₆ alkyl-C(O)N(R^(a))(R^(b)),    —C(O)N(R^(a))(R^(b)), N(R^(a))(R^(b))—C₁₋₆ alkyl-, wherein R^(a) and    R^(b) are independently H, OH (R^(a) and R^(b) are not both OH),    C₂₋₆ hydroxyalkyl, or C₁₋₆ alkyl or R^(a) and R^(b) together with    the nitrogen atom to which they are both linked form a 3, 4, 5 or    6-membered heterocycle, wherein optionally any two adjacent R₇-R₁₁    groups together form a 3, 4, 5 or 6-membered carbocycle or    heterocycle; and-   B, D, W, X, Y and Z are independently C or N, provided that at least    one of B and D is N, and at least one of W, X, Y and Z is N, and    wherein when B, D, W, X, Y or Z is N, then there is no substituent    at the N.

In a specific embodiment, preferably when R₉ is H, then at least one ofR₈ and R₁₀ is not H, more preferably R₉ is other than H.

In some specific embodiments, B is C and D is N. In other specificembodiments, B is N and D is C. In preferred embodiments, both B and Dare N.

In one embodiment of the compounds of Formula Va,

-   R₂ is H; halo; N₃;-   C₁₋₆ alkyl (preferably C₁₋₃ alkyl, more preferably CH₃) optionally    substituted with OH or halo (preferably F, e.g., monofluoro,    difluoro, or trifluoro);-   —XR_(2a) wherein X is S or O, and R_(2a) is C₁₋₆ alkyl (preferably    C₁₋₃ alkyl, more preferably CH₃) optionally substituted with OH or    halo (preferably F, e.g., monofluoro-, difluoro-, or    trifluoro-substituted);-   —CO₂R^(d), wherein R^(d) is C₁₋₃ alkyl, preferably methyl or ethyl;    or

—N(R^(a))(R^(b)) wherein R^(a) and R^(b) are independently H, OH (R^(a)and R^(b) are not both OH), C₁₋₃ alkyl (preferably CH₃), C₁₋₆hydroxyalkyl (preferably C₂₋₃ hydroxyalkyl, more preferably —CH₂CH₂OH),or C₁₋₆ alkyl (preferably C₁₋₃ alkyl, more preferably CH₃) that isoptionally substituted with —N(R^(e))(R^(f)) wherein R^(e) and R^(f) areindependently H, OH (R^(e) and R^(f) are not both OH), C₁₋₃ alkyl(preferably CH₃), or C₂₋₃ hydroxyalkyl (preferably —CH₂CH2OH), andwherein optionally R^(a) and R^(b) together may form a 3, 4, 5 or6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, andmorpholinyl).

In another embodiment of the compound of Formula Va, R₂ is H, methyl,ethyl, Cl, F, fluoromethyl (CH₂F, CHF₂, CF₃), C₁₋₃ hydroxyalkyl(preferably CH₂OH or CH₂CH₂OH), NH₂, NH₂OH, —NHCH₂CH₂OH, NHCH₃, N(CH₃)₂,N₃, morpholino, OCH₃, OC₂H₅, or SCH₃.

In preferred embodiment, R₂ is H, methyl, Cl, —CH₂OH, —NH₂, —NHCH₃,—NHCH₂CH₂OH, —OCH₃, —SCH₃, or —CH₂F.

In one embodiment, R₉ is selected from the group consisting of H; OH;Cl; N₃; C₁₋₃ alkyl (preferably methyl or ethyl) or C₁₋₃ haloalkyl(preferably monofluoromethyl, difluoromethyl, trifluoromethyl);—OR_(9a), wherein R_(9a) is C₁₋₃ alkyl (i.e., methyl, ethyl, propyl,isopropyl) or C₁₋₃ haloalkyl (e.g., fluoroalkyl, preferablyfluoromethyl, i.e., CH₂F, CHF₂, CF₃); —N(R^(a))(R^(b)) wherein R^(a) andR^(b) are independently H or C₁₋₃ alkyl; or —COOR_(9b), wherein R_(9b)is C₁₋₃ alkyl (preferably methyl or ethyl); and optionally R₉ and one ofR₈ and R₁₀ together form a 3, 4, 5, or 6-membered heterocycle.

In another embodiment, R₉ is —OCH₃, —OC₂H₅, —N(CH₃)₂, —CO₂CH₃, —OCHF₂,or N₃.

In yet another embodiment, when R₉ is H, then at least one of R₈ and R₁₀is not H. In another embodiment, when R₉ is alkyl, then R₂ is not H.

In a specific embodiment, compounds of the invention include compoundsof Formula Va or pharmaceutically acceptable salts or solvates thereof,wherein:

-   R₁ is C₁₋₂ alkyl, and preferably R₁ is methyl;-   R₅ is H or F, preferably H;-   R₂-R₄, R₆, R₈-R₁₀, R₁₂ and R₁₃ are independently H; halo; N₃;    -   C₁₋₆ alkyl (preferably C₁₋₃ alkyl, more preferably CH₃)        optionally substituted with 1, 2 or 3 substituents, each        substituent being independently OH, halo, C₁₋₃ alkoxy, (halo)        C₁₋₃ alkoxy, —N(R^(a))(R^(b)) where R^(a) and R^(b) are        independently H, OH (R^(a) and R^(b) are not both OH), C₂₋₆        hydroxyalkyl, or C₁₋₆ alkyl or R^(a) and R^(b) together with the        nitrogen atom to which they are both linked form a 3, 4, 5 or        6-membered heterocycle;    -   —XR^(c) wherein X is S or O and R^(c) is C₁₋₆ alkyl (preferably        C₁₋₃ alkyl, more preferably CH₃) optionally substituted with        with 1, 2 or 3 substituents, each substituent being        independently OH, halo, C₁₋₃ alkoxy, C₂-C₄ alkenyl, C₂-C₄        alkynyl, —N(R^(a))(R^(b)) where R^(a) and R^(b) are        independently H, OH (R^(a) and R^(b) are not both OH), C₂₋₆        hydroxyalkyl, or C₁₋₆ alkyl or R^(a) and R^(b) together with the        nitrogen atom to which they are both linked form a 3, 4, 5 or        6-membered heterocycle;    -   —(C₀₋₃ alkyl)CO₂R^(d), wherein R^(d) is an C₁₋₆ alkyl        (preferably C₁₋₃ alkyl, more preferably methyl or ethyl)        optionally substituted with 1, 2 or 3 substituents, each        substituent being independently OH, halo, C₁₋₃ alkoxy (e.g.,        fluoroalkoxy), —N(R^(a))(R^(b)) where R^(a) and R^(b) are        independently H, OH (R^(a) and R^(b) are not both OH), C₂₋₆        hydroxyalkyl, or C₁₋₆ alkyl or R^(a) and R^(b) together with the        nitrogen atom to which they are both linked form a 3, 4, 5 or        6-membered heterocycle; or    -   —N(R^(a))(R^(b)) where R^(a) and R^(b) are independently H; OH        (R^(a) and R^(b) are not both OH); C₂₋₆ hydroxyalkyl; C₁₋₆        alkyl; or C₁₋₆ alkyl substituted with —N(R^(e))(R^(f)) where        R^(e) and R^(f) are independently H, OH (R^(e) and R^(f) are not        both OH), or C₁₋₃ alkyl; wherein optionally R^(a) and R^(b)        together, and/or R^(e) and R^(f) together, with the nitrogen        atom to which they are linked form a 3, 4, 5 or 6-membered        heterocycle; preferably when R₉ is H, at least one of R₈ and R₁₀        is not H, more preferably R₉ is other than H.-   R₇ and R₁₁ are independently H, halo (preferably F or Cl, more    preferably F), C₁₋₃ alkyl (preferably CH₃), or C₁₋₄ alkoxy    (preferably OCH3); and-   B, D, W, X, Y, and Z are as defined above, provided that when B, D,    W, X, Y or Z is N there is no substituent at the N.

In another preferred embodiment of the compounds of Formula Va,

-   R₁ is methyl or ethyl, more preferably methyl;-   R₂ is H; halo; N₃;-   C₁₋₆ alkyl (preferably C₁₋₃ alkyl, more preferably CH₃) optionally    substituted with OH or halo (preferably F, e.g., monofluoro,    difluoro, or trifluoro);-   —XR_(2a) wherein X is S or O, and R_(2a) is C₁₋₆ alkyl (preferably    C₁₋₃ alkyl, more preferably CH₃) optionally substituted with OH or    halo (preferably F, e.g., monofluoro-, difluoro-, or    trifluoro-substituted);-   —CO₂R^(d), wherein R^(d) is C₁₋₃ alkyl, preferably methyl or ethyl;    or

—N(R¹)(R^(b)) wherein R^(a) and R^(b) are independently H, OH (R^(a) andR^(b) are not both OH), C₁₋₃ alkyl (preferably CH₃), C₁₋₆ hydroxyalkyl(preferably C₂₋₃ hydroxyalkyl, more preferably —CH₂CH₂OH), or C₁₋₆ alkyl(preferably C₁₋₃ alkyl, more preferably CH₃) that is optionallysubstituted with —N(R^(e))(R^(f)) wherein R^(e) and R^(f) areindependently H, OH (R^(e) and R^(f) are not both OH), C₁₋₃ alkyl(preferably CH₃), or C₂₋₃ hydroxyalkyl (preferably —CH₂CH2OH), andwherein optionally R^(a) and R^(b) together may form a 3, 4, 5 or6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, andmorpholinyl);

-   R₃ and R₁₂ are independently H; halo; C₁₋₃ alkyl; or C₁₋₃ alkoxy;-   R₄, R₆, and R₁₃ are independently H; halo (preferably F or Cl); N₃;    C₁₋₃ alkyl (preferably CH₃); C₁₋₃ alkoxy (preferably OCH₃); or    —N(R^(a))(R^(b)) wherein R^(a) and R^(b) are independently H, OH,    C₁₋₃ alkyl, hydroxy-C₁₋₃ alkyl, and optionally R^(a) and R^(b)    together may form a 3, 4, 5 or 6-membered heterocycle (e.g.,    piperidinyl, pyrrolidinyl, and morpholinyl), and wherein R^(a) and    R^(b) are not both OH;-   R₅ is H;-   R₇ and R₁₁ are independently H, halo (preferably F), CH₃, or OCH₃;-   R₈ and R₁₀ are independently H; halo (preferably F or Cl, more    preferably F); C₁₋₃ alkyl (preferably CH₃); C₁₋₃ alkoxy (preferably    OCH₃); and-   R₉ is selected from the group: H; OH; Cl; N₃; C₁₋₃ alkyl (preferably    methyl or ethyl) or C₁₋₃ haloalkyl (preferably monofluoromethyl,    difluoromethyl, trifluoromethyl); —OR_(9a), wherein R_(9a) is C₁₋₃    alkyl (i.e., methyl, ethyl, propyl, isopropyl) or C₁₋₃ haloalkyl    (e.g., fluoroalkyl, preferably fluoromethyl, i.e., CH₂F, CHF₂, CF₃);    —N(R^(a))(R^(b)) wherein R^(a) and R^(b) are independently H or C₁₋₃    alkyl; or —COOR_(9b), wherein R_(9b) is C₁₋₃ alkyl (preferably    methyl or ethyl); and optionally R₉ and one of R₈ and R₁₀ together    form a 3, 4, 5, or 6-membered heterocycle; preferably when R₉ is H,    at least one of R₈ and R₁₀ is not H, more preferably R₉ is other    than H; and-   B, D, W, X, Y, and Z are independently C or N, provided that at    least one of B and D is N, and at least one of W, X, Y, and Z is N,    wherein when B, D, W, X, Y, or Z is nitrogen, then there is no    substituent at the N.

In more preferred embodiment, compounds of the invention includecompounds of Formula Va or pharmaceutically acceptable salts or solvatesthereof, wherein:

-   R₁ is methyl or ethyl, preferably methyl;-   R₂ is H, methyl, ethyl, Cl, F, fluoromethyl (CH₂F, CHF₂, CF₃), C₁₋₃    hydroxyalkyl (preferably CH₂OH or CH₂CH₂OH), NH₂, NH₂OH,    —NHCH₂CH₂OH, NHCH₃, N(CH₃)₂, N₃, morpholino, OCH₃, OC₂H₅, or SCH₃;-   R₃ and R₁₂ are independently H, CH₃, OCH₃, F, or Cl;-   R₄, R₆, and R₁₃ are independently H, CH₃, NH₂, N₃, F, or Cl;-   R₅ is H;-   R₇ and R₁₁ are independently H, F, or OCH₃;-   R₈ and R₁₀ are independently H, F, Cl, or OCH₃;-   R₉ is selected from the group of consisting of H; OH; Cl; N₃; C₁₋₃    alkyl (preferably methyl or ethyl); C₁₋₃ haloalkyl (preferably    monofluoromethyl, difluoromethyl, trifluoromethyl); —OR_(9a) where    R_(9a) is C₁₋₃ alkyl (i.e., methyl, ethyl, propyl, isopropyl) or    C₁₋₃ haloalkyl (e.g., fluoroalkyl, preferably fluoromethyl, i.e.,    CH₂F, CHF₂, CF₃); —N(R^(a))(R^(b)) wherein R^(a) and R^(b) are    independently H or C₁₋₃ alkyl; and —COOR_(9b), wherein R_(9b) is    C₁₋₃ alkyl (preferably methyl or ethyl), and optionally R₉ and one    of R₈ and R₁₀ together form a 3, 4, 5, or 6-membered heterocycle;    preferably when R₉ is H, at least one of R₈ and R₁₀ is not H, more    preferably R₉ is other than H; and-   B, D, W, X, Y and Z are as defined above, provided that when B, D,    W, X, Y or Z is N, then there is no substituent at the N. Preferably    in this embodiment, when R₉ is alkyl, R₂ not H.

In a even more preferred embodiment, compounds of the invention includecompounds of Formula Va or pharmaceutically acceptable salts or solvatesthereof, wherein R₁ is methyl; R₂ is H, methyl, Cl, —CH₂OH, —NH₂,—NHCH₃, —NHCH₂CH₂OH, —OCH₃, —SCH₃, or —CH₂F; R₃ and R₁₂ areindependently H, methyl, —OCH₃, or Cl; R₄ is H, methyl, or NH₂; R₅ is H;R₆ and R₁₃ are independently H or methyl; R₇ and R₁₁ are independently Hor F; R₈ and R₁₀ are independently H, or F or OCH₃; and R₉ is —OCH₃,—OC₂H₅, —N(CH₃)₂, —CO₂CH₃, —OCHF₂, or N₃; and B, D, W, X, Y, and Z areas defined above, provided that when B, D, W, X, Y, or Z is N, thenthere is no substituent at the N.

In all embodiments of the compounds of Formula Va, it is preferred thatone of W, X, Y and Z is N, or two of W, X, Y and Z are N.

Another group of preferred compounds of the present invention are thoserepresented by Formula V with the proviso that both B and D arenitrogen. Specifically such compounds are represented by Formula Vb:

or pharmaceutically acceptable salts or solvates thereof, wherein:

-   R₁ is methyl or ethyl, preferably methyl;-   R₅ is H, F, Cl, N₃, methyl, methoxy or NH₂, with the proviso that    when R₅ is methoxy, R₁ is methyl; Preferably R₅ is H, F or N₃, more    preferably H or F, and most preferably H;-   R₂-R₄, and R₆-R₁₁ are independently H, halo, N₃, OH, thiol, nitro,    CN, NH₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆    alkylthiol, halo-C₁₋₆ alkyl, C₂₋₆ alkenyl-O—, C₂₋₆ alkynyl-O—,    hydroxy-C₁₋₆ alkyl, C₁₋₆ alkoxy-C₁₋₆ alkyl, C₁₋₆ acyl, C₁₋₆ acyloxy,    —C₁₋₆ alkyl-C(O)O—C₁₋₆ alkyl, —C(O)O—C₁₋₆ alkyl, C₁₋₆    alkyl-C(O)O—C₁₋₆ alkyl-, C₁₋₆ acylamido, —N(R^(a))(R^(b)), —C₁₋₆    alkyl-C(O)N(R^(a))(R^(b)), —C(O)N(R^(a))(R^(b)),    N(R^(a))(R^(b))—C₁₋₆ alkyl-, 3, 4, 5, or 6-membered carbocycle,    heterocycle, aryl, or heteroaryl, wherein R^(a) and R^(b) are    independently H, OH (R^(a) and R^(b) are not both OH), C₂₋₆    hydroxyalkyl, or C₁₋₆ alkyl, or R^(a) and R^(b) together with the    nitrogen atom to which they are both linked form a 3, 4, 5 or    6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and    morpholinyl); wherein any of the groups is optionally substituted    with 1-3 substituents wherein each substituent is independently    halo, N₃, OH, thiol, nitro, CN, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆    alkynyl, C₁₋₆ alkoxy, C₁₋₆ alkylthiol, C₂₋₆ alkenyl-O—, C₂₋₆    alkynyl-O—, hydroxy-C₁₋₆ alkyl, C₁₋₆ alkoxy-C₁₋₆ alkyl, C₁₋₆ acyl,    C₁₋₆ acyloxy, —C₁₋₆ alkyl-C(O)O—C₁₋₆ alkyl, —C(O)O—C₁₋₆ alkyl, C₁₋₆    alkyl-C(O)O—C₁₋₆ alkyl-, C₁₋₆ acylamido, —N(R^(a))(R^(b)), —C₁₋₆    alkyl-C(O)N(R^(a))(R^(b)), —C(O)N(R^(a))(R^(b)),    N(R^(a))(R^(b))—C₁₋₆ alkyl-, wherein R^(a) and R^(b) are    independently H, OH (R^(a) and R^(b) are not both OH), C₂₋₆    hydroxyalkyl, or C₁₋₆ alkyl or R^(a) and R^(b) together with the    nitrogen atom to which they are both linked form a 3, 4, 5 or    6-membered heterocycle, wherein optionally any two adjacent R₇-R₁₁    groups together form a 3, 4, 5 or 6-membered carbocycle or    heterocycle; and-   Q, T, U, V, W, X, Y and Z are independently C or N, provided that at    least one of W, X, Y and Z is N, and wherein when Q, T, U, V, W, X,    Y or Z is N, then there is no substituent at the N.

In a specific embodiment, preferably when R₉ is H, then at least one ofR₈ and R₁₀ is not H, more preferably R₉ is other than H.

In one embodiment of the compounds of Formula Vb,

-   R₂ is H; halo; N₃;-   C₁₋₆ alkyl (preferably C₁₋₃ alkyl, more preferably CH₃) optionally    substituted with OH or halo (preferably F, e.g., monofluoro,    difluoro, or trifluoro);-   —XR_(2a) wherein X is S or O, and R_(2a) is C₁₋₆ alkyl (preferably    C₁₋₃ alkyl, more preferably CH₃) optionally substituted with OH or    halo (preferably F, e.g., monofluoro-, difluoro-, or    trifluoro-substituted);-   —CO₂R^(d), wherein R^(d) is C₁₋₃ alkyl, preferably methyl or ethyl;    or

—N(R^(a))(R^(b)) wherein R^(a) and R^(b) are independently H, OH (R^(a)and R^(b) are not both OH), C₁₋₃ alkyl (preferably CH₃), C₁₋₆hydroxyalkyl (preferably C₂₋₃ hydroxyalkyl, more preferably —CH₂CH₂OH),or C₁₋₆ alkyl (preferably C₁₋₃ alkyl, more preferably CH₃) that isoptionally substituted with —N(R^(e))(R^(f)) wherein R^(e) and R^(f) areindependently H, OH (R^(e) and R^(f) are not both OH), C₁₋₃ alkyl(preferably CH₃), or C₂₋₃ hydroxyalkyl (preferably —CH₂CH2OH), andwherein optionally R^(a) and R^(b) together may form a 3, 4, 5 or6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, andmorpholinyl).

In another embodiment of the compound of Formula V, R₂ is H, methyl,ethyl, Cl, F, fluoromethyl (CH₂F, CHF₂, CF₃), C₁₋₃ hydroxyalkyl(preferably CH₂OH or CH₂CH₂OH), NH₂, NH₂OH, —NHCH₂CH₂OH, NHCH₃, N(CH₃)₂,N₃, morpholino, OCH₃, OC₂H₅, or SCH₃.

In preferred embodiment, R₂ is H, methyl, Cl, —CH₂OH, —NH₂, —NHCH₃,—NHCH₂CH₂OH, —OCH₃, —SCH₃, or —CH₂F.

In one embodiment, R₉ is selected from the group consisting of H; OH;Cl; N₃; C₁₋₃ alkyl (preferably methyl or ethyl) or C₁₋₃ haloalkyl(preferably monofluoromethyl, difluoromethyl, trifluoromethyl);—OR_(9a), wherein R_(9a) is C₁₋₃ alkyl (i.e., methyl, ethyl, propyl,isopropyl) or C₁₋₃ haloalkyl (e.g., fluoroalkyl, preferablyfluoromethyl, i.e., CH₂F, CHF₂, CF₃); —N(R^(a))(R^(b)) wherein R^(a) andR^(b) are independently H or C₁₋₃ alkyl; or —COOR_(9b), wherein R_(9b)is C₁₋₃ alkyl (preferably methyl or ethyl); and optionally R₉ and one ofR₈ and R₁₀ together form a 3, 4, 5, or 6-membered heterocycle.

In another embodiment, R₉ is —OCH₃, —OC₂H₅, —N(CH₃)₂, —CO₂CH₃, —OCHF₂,or N₃.

In yet another embodiment, when R₉ is H, then at least one of R₈ and R₁₀is not H. In another embodiment, when R₉ is alkyl, then R₂ is not H.

In a specific embodiment, compounds of the invention include compoundsof Formula Vb or pharmaceutically acceptable salts or solvates thereof,wherein:

-   R₁ is C₁₋₂ alkyl, and preferably R₁ is methyl;-   R₅ is H or F, preferably H;-   R₂-R₄, R₆, R₈-R₁₀ are independently H; halo; N₃;    -   C₁₋₆ alkyl (preferably C₁₋₃ alkyl, more preferably CH₃)        optionally substituted with 1, 2 or 3 substituents, each        substituent being independently OH, halo, C₁₋₃ alkoxy, (halo)        C₁₋₃ alkoxy, —N(R^(a))(R^(b)) where R^(a) and R^(b) are        independently H, OH (R^(a) and R^(b) are not both OH), C₂₋₆        hydroxyalkyl, or C₁₋₆ alkyl or R^(a) and R^(b) together with the        nitrogen atom to which they are both linked form a 3, 4, 5 or        6-membered heterocycle;    -   —XR^(c) wherein X is S or O and R^(c) is C₁₋₆ alkyl (preferably        C₁₋₃ alkyl, more preferably CH₃) optionally substituted with        with 1, 2 or 3 substituents, each substituent being        independently OH, halo, C₁₋₃ alkoxy, C₂-C₄ alkenyl, C₂-C₄        alkynyl, —N(R^(a))(R^(b)) where R^(a) and R^(b) are        independently H, OH (R^(a) and R^(b) are not both OH), C₂₋₆        hydroxyalkyl, or C₁₋₆ alkyl or R^(a) and R^(b) together with the        nitrogen atom to which they are both linked form a 3, 4, 5 or        6-membered heterocycle;    -   —(C₀₋₃ alkyl)CO₂R^(d), wherein R^(d) is an C₁₋₆ alkyl        (preferably C₁₋₃ alkyl, more preferably methyl or ethyl)        optionally substituted with 1, 2 or 3 substituents, each        substituent being independently OH, halo, C₁₋₃ alkoxy (e.g.,        fluoroalkoxy), —N(R^(a))(R^(b)) where R^(a) and R^(b) are        independently H, OH (R^(a) and R^(b) are not both OH), C₂₋₆        hydroxyalkyl, or C₁₋₆ alkyl or R^(a) and R^(b) together with the        nitrogen atom to which they are both linked form a 3, 4, 5 or        6-membered heterocycle; or    -   —N(R^(a))(R^(b)) where R^(a) and R^(b) are independently H; OH        (R^(a) and R^(b) are not both OH); C₂₋₆ hydroxyalkyl; C₁₋₆        alkyl; or C₁₋₆ alkyl substituted with —N(R^(e))(R^(f)) where        R^(e) and R^(f) are independently H, OH (R^(e) and R^(f) are not        both OH), or C₁₋₃ alkyl; wherein optionally R^(a) and R^(b)        together, and/or R^(e) and R^(f) together, with the nitrogen        atom to which they are linked to form a 3, 4, 5 or 6-membered        heterocycle; preferably when R₉ is H, at least one of R₈ and R₁₀        is not H, more preferably R₉ is other than H.-   R₇ and R₁₁ are independently H, halo (preferably F or Cl, more    preferably F), C₁₋₃ alkyl (preferably CH₃), or C₁₋₄ alkoxy    (preferably OCH3); and-   Q, T, U, V, W, X, Y, and Z are as defined above, provided that when    Q, T, U, V, W, X, Y or Z is N there is no substituent at the N.

In another preferred embodiment of the compounds of Formula Vb,

-   R₁ is methyl or ethyl, more preferably methyl;-   R₂ is H; halo; N₃;-   C₁₋₆ alkyl (preferably C₁₋₃ alkyl, more preferably CH₃) optionally    substituted with OH or halo (preferably F, e.g., monofluoro,    difluoro, or trifluoro);-   —XR_(2a) wherein X is S or O, and R_(2a) is C₁₋₆ alkyl (preferably    C₁₋₃ alkyl, more preferably CH₃) optionally substituted with OH or    halo (preferably F, e.g., monofluoro-, difluoro-, or    trifluoro-substituted);-   —CO₂R^(d), wherein R^(d) is C₁₋₃ alkyl, preferably methyl or ethyl;    or

—N(R^(a))(R^(b)) wherein R^(a) and R^(b) are independently H, OH (R^(a)and R^(b) are not both OH), C₁₋₃ alkyl (preferably CH₃), C₁₋₆hydroxyalkyl (preferably C₂₋₃ hydroxyalkyl, more preferably —CH₂CH₂OH),or C₁₋₆ alkyl (preferably C₁₋₃ alkyl, more preferably CH₃) that isoptionally substituted with —N(R^(e))(R^(f)) wherein R^(e) and R^(f) areindependently H, OH (R^(e) and R^(f) are not both OH), C₁₋₃ alkyl(preferably CH₃), or C₂₋₃ hydroxyalkyl (preferably —CH₂CH2OH), andwherein optionally R^(a) and R^(b) together may form a 3, 4, 5 or6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, andmorpholinyl);

-   R₃ is H; halo; C₁₋₃ alkyl; or C₁₋₃ alkoxy;-   R₄, and R₆ are independently H; halo (preferably F or Cl); N₃; C₁₋₃    alkyl (preferably CH₃); C₁₋₃ alkoxy (preferably OCH₃); or    —N(R^(a))(R^(b)) wherein R^(a) and R^(b) are independently H, OH,    C₁₋₃ alkyl, hydroxy-C₁₋₃ alkyl, and optionally R^(a) and R^(b)    together may form a 3, 4, 5 or 6-membered heterocycle (e.g.,    piperidinyl, pyrrolidinyl, and morpholinyl), and wherein R^(a) and    R^(b) are not both OH;-   R₅ is H;-   R₇ and R₁₁ are independently H, halo (preferably F), CH₃, or OCH₃;-   R₈ and R₁₀ are independently H; halo (preferably F or Cl, more    preferably F); C₁₋₃ alkyl (preferably CH₃); C₁₋₃ alkoxy (preferably    OCH₃); and-   R₉ is selected from the group: H; OH; Cl; N₃; C₁₋₃ alkyl (preferably    methyl or ethyl) or C₁₋₃ haloalkyl (preferably monofluoromethyl,    difluoromethyl, trifluoromethyl); —OR_(9a), wherein R_(9a) is C₁₋₃    alkyl (i.e., methyl, ethyl, propyl, isopropyl) or C₁₋₃ haloalkyl    (e.g., fluoroalkyl, preferably fluoromethyl, i.e., CH₂F, CHF₂, CF₃);    —N(R^(a))(R^(b)) wherein R^(a) and R^(b) are independently H or C₁₋₃    alkyl; or —COOR_(9b), wherein R_(9b) is C₁₋₃ alkyl (preferably    methyl or ethyl); and optionally R₉ and one of R₈ and R₁₀ together    form a 3, 4, 5, or 6-membered heterocycle; preferably when R₉ is H,    at least one of R₈ and R₁₀ is not H, more preferably R₉ is other    than H; and-   Q, T, U, V, W, X, Y, and Z are independently C or N, provided that    at least one of W, X, Y, and Z is N, wherein when Q, T, U, V, W, X,    Y, or Z is nitrogen, then there is no substituent at the N.

In more preferred embodiment, compounds of the invention includecompounds of Formula Vb or pharmaceutically acceptable salts or solvatesthereof, wherein:

-   R₁ is methyl or ethyl, preferably methyl;-   R₂ is H, methyl, ethyl, Cl, F, fluoromethyl (CH₂F, CHF₂, CF₃), C₁₋₃    hydroxyalkyl (preferably CH₂OH or CH₂CH₂OH), NH₂, NH₂OH,    —NHCH₂CH₂OH, NHCH₃, N(CH₃)₂, N₃, morpholino, OCH₃, OC₂H₅, or SCH₃;-   R₃ is H, CH₃, OCH₃, F, or Cl;-   R₄, and R₆ are independently H, CH₃, NH₂, N₃, F, or Cl;-   R₅ is H;-   R₇ and R₁₁ are independently H, F, or OCH₃;-   R₈ and R₁₀ are independently H, F, Cl, or OCH₃;-   R₉ is selected from the group of consisting of H; OH; Cl; N₃; C₁₋₃    alkyl (preferably methyl or ethyl); C₁₋₃ haloalkyl (preferably    monofluoromethyl, difluoromethyl, trifluoromethyl); —OR_(9a) where    R_(9a) is C₁₋₃ alkyl (i.e., methyl, ethyl, propyl, isopropyl) or    C₁₋₃ haloalkyl (e.g., fluoroalkyl, preferably fluoromethyl, i.e.,    CH₂F, CHF₂, CF₃); —N(R^(a))(R^(b)) wherein R^(a) and R^(b) are    independently H or C₁₋₃ alkyl; and —COOR_(9b), wherein R_(9b) is    C₁₋₃ alkyl (preferably methyl or ethyl), and optionally R₉ and one    of R₈ and R₁₀ together form a 3, 4, 5, or 6-membered heterocycle;    preferably when R₉ is H, at least one of R₈ and R₁₀ is not H, more    preferably R₉ is other than H; and-   Q, T, U, V, W, X, Y and Z are as defined above, provided that when    Q, T, U, V, W, X, Y or Z is N, then there is no substituent at    the N. Preferably in this embodiment, when R₉ is alkyl, then R₂ is    not H.

In an even more preferred embodiment, compounds of the invention includecompounds of Formula Vb or pharmaceutically acceptable salts or solvatesthereof, wherein R₁ is methyl; R₂ is H, methyl, Cl, —CH₂OH, —NH₂,—NHCH₃, —NHCH₂CH₂OH, —OCH₃, —SCH₃, or —CH₂F; R₃ is H, methyl, —OCH₃, orCl; R₄ is H, methyl, or NH₂; R₅ is H; R₆ is H or methyl; R₇ and R₁₁ areindependently H or F; R₈ and R₁₀ are independently H, or F or OCH₃; andR₉ is —OCH₃, —OC₂H₅, —N(CH₃)₂, —CO₂CH₃, —OCHF₂, or N₃; and Q, T, U, V,W, X, Y, and Z are as defined above, provided that when Q, T, U, V, W,X, Y, or Z is N, then there is no substituent at the N.

In all embodiments of the compounds of Formula Vb, it is preferred thatone of W, X, Y and Z is N, or two of W, X, Y and Z are N. In any of theembodiments, preferably one or two of Q, T, U and V are N. For example,Q and V can be both N, and T and U are C.

Another specifical group of compounds of Formula V include thoserepresented by Formula Vc:

or pharmaceutically acceptable saltsor solvates thereof, wherein:

-   R₁ is methyl or ethyl, preferably methyl;-   R₅ is H, F, Cl, N₃, methyl, methoxy or NH₂, with the proviso that    when R₅ is methoxy, R₁ is methyl; preferably R₅ is H, F or N₃, more    preferably H or F, and most preferably H;-   R₂-R₄, and R₆-R₁₁ are independently H, halo, N₃, OH, thiol, nitro,    CN, NH₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆    alkylthiol, halo-C₁₋₆ alkyl, C₂₋₆ alkenyl-O—, C₂₋₆ alkynyl-O—,    hydroxy-C₁₋₆ alkyl, C₁₋₆ alkoxy-C₁₋₆ alkyl, C₁₋₆ acyl, C₁₋₆ acyloxy,    —C₁₋₆ alkyl-C(O)O—C₁₋₆ alkyl, —C(O)O—C₁₋₆ alkyl, C₁₋₆    alkyl-C(O)O—C₁₋₆ alkyl, C₁₋₆ acylamido, —N(R^(a))(R^(b)), —C₁₋₆    alkyl-C(O)N(R^(a))(R^(b)), —C(O)N(R^(a))(R^(b)),    N(R^(a))(R^(b))—C₁₋₆ alkyl-, 3, 4, 5, or 6-membered carbocycle,    heterocycle, aryl, or heteroaryl, wherein R^(a) and R^(b) are    independently H, OH (R^(a) and R^(b) are not both OH), C₂₋₆    hydroxyalkyl, or C₁₋₆ alkyl, or R^(a) and R^(b) together with the    nitrogen atom to which they are both linked form a 3, 4, 5 or    6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and    morpholinyl); wherein any of the groups is optionally substituted    with 1-3 substituents wherein each substituent is independently    halo, N₃, OH, thiol, nitro, CN, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆    alkynyl, C₁₋₆ alkoxy, C₁₋₆ alkylthiol, C₂₋₆ alkenyl-O—, C₂₋₆    alkynyl-O—, hydroxy-C₁₋₆ alkyl, C₁₋₆ alkoxy-C₁₋₆ alkyl, C₁₋₆ acyl,    C₁₋₆ acyloxy, —C₁₋₆ alkyl-C(O)O—C₁₋₆ alkyl, —C(O)O—C₁₋₆ alkyl, C₁₋₆    alkyl-C(O)O—C₁₋₆ alkyl-, C₁₋₆ acylamido, —N(R^(a))(R^(b)), —C₁₋₆    alkyl-C(O)N(R^(a))(R^(b)), —C(O)N(R^(a))(R^(b)),    N(R^(a))(R^(b))—C₁₋₆ alkyl-, wherein R^(a) and R^(b) are    independently H, OH (R^(a) and R^(b) are not both OH), C₂₋₆    hydroxyalkyl, or C₁₋₆ alkyl or R^(a) and R^(b) together with the    nitrogen atom to which they are both linked form a 3, 4, 5 or    6-membered heterocycle, wherein optionally any two adjacent R₇-R₁₁    groups together form a 3, 4, 5 or 6-membered carbocycle or    heterocycle; and-   W, X, Y and Z are independently C or N, provided that at least one    of W, X, Y and Z is N, and wherein when W, X, Y or Z is N, then    there is no substituent at the N.

In a specific embodiment, preferably when R₉ is H, then at least one ofR₈ and R₁₀ is not H, more preferably R₉ is other than H.

In one embodiment of the compounds of Formula Vc,

-   R₂ is H; halo; N₃;-   C₁₋₆ alkyl (preferably C₁₋₃ alkyl, more preferably CH₃) optionally    substituted with OH or halo (preferably F, e.g., monofluoro,    difluoro, or trifluoro);-   —XR_(2a) wherein X is S or O, and R_(2a) is C₁₋₆ alkyl (preferably    C₁₋₃ alkyl, more preferably CH₃) optionally substituted with OH or    halo (preferably F, e.g., monofluoro-, difluoro-, or    trifluoro-substituted);-   —CO₂R^(d), wherein R^(d) is C₁₋₃ alkyl, preferably methyl or ethyl;    or

—N(R^(a))(R^(b)) wherein R^(a) and R^(b) are independently H, OH (R^(a)and R^(b) are not both OH), C₁₋₃ alkyl (preferably CH₃), C₁₋₆hydroxyalkyl (preferably C₂₋₃ hydroxyalkyl, more preferably —CH₂CH₂OH),or C₁₋₆ alkyl (preferably C₁₋₃ alkyl, more preferably CH₃) that isoptionally substituted with —N(R^(e))(R^(f)) wherein R^(e) and R^(f) areindependently H, OH (R^(e) and R^(f) are not both OH), C₁₋₃ alkyl(preferably CH₃), or C₂₋₃ hydroxyalkyl (preferably —CH₂CH2OH), andwherein optionally R^(a) and R^(b) together may form a 3, 4, 5 or6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, andmorpholinyl).

In another embodiment of the compound of Formula Vc, R₂ is H, methyl,ethyl, Cl, F, fluoromethyl (CH₂F, CHF₂, CF₃), C₁₋₃ hydroxyalkyl(preferably CH₂OH or CH₂CH₂OH), NH₂, NH₂OH, —NHCH₂CH₂OH, NHCH₃, N(CH₃)₂,N₃, morpholino, OCH₃, OC₂H₅, or SCH₃.

In preferred embodiment, R₂ is H, methyl, Cl, —CH₂OH, —NH₂, —NHCH₃,—NHCH₂CH₂OH, —OCH₃, —SCH₃, or —CH₂F.

In one embodiment, R₉ is selected from the group consisting of H; OH;Cl; N₃; C₁₋₃ alkyl (preferably methyl or ethyl) or C₁₋₃ haloalkyl(preferably monofluoromethyl, difluoromethyl, trifluoromethyl);—OR_(9a), wherein R_(9a) is C₁₋₃ alkyl (i.e., methyl, ethyl, propyl,isopropyl) or C₁₋₃ haloalkyl (e.g., fluoroalkyl, preferablyfluoromethyl, i.e., CH₂F, CHF₂, CF₃); —N(R^(a))(R^(b)) wherein R^(a) andR^(b) are independently H or C₁₋₃ alkyl; or —COOR_(9b), wherein R_(9b)is C₁₋₃ alkyl (preferably methyl or ethyl); and optionally R₉ and one ofR₈ and R₁₀ together form a 3, 4, 5, or 6-membered heterocycle.

In another embodiment, R₉ is —OCH₃, —OC₂H₅, —N(CH₃)₂, —CO₂CH₃, —OCHF₂,or N₃.

In yet another embodiment, when R₉ is H, then at least one of R₈ and R₁₀is not H. In another embodiment, when R₉ is alkyl, then R₂ is not H.

In a specific embodiment, compounds of the invention include compoundsof Formula Vc or pharmaceutically acceptable salts or solvates thereof,wherein:

-   R₁ is C₁₋₂ alkyl, and preferably R₁ is methyl;-   R₅ is H or F, preferably H;-   R₂-R₄, R₆, R₈-R₁₀ are independently H; halo; N₃;    -   C₁₋₆ alkyl (preferably C₁₋₃ alkyl, more preferably CH₃)        optionally substituted with 1, 2 or 3 substituents, each        substituent being independently OH, halo, C₁₋₃ alkoxy, (halo)        C₁₋₃ alkoxy, —N(R^(a))(R^(b)) where R^(a) and R^(b) are        independently H, OH (R^(a) and R^(b) are not both OH), C₂₋₆        hydroxyalkyl, or C₁₋₆ alkyl or R^(a) and R^(b) together with the        nitrogen atom to which they are both linked form a 3, 4, 5 or        6-membered heterocycle;    -   —XR^(c) wherein X is S or O and R^(c) is C₁₋₆ alkyl (preferably        C₁₋₃ alkyl, more preferably CH₃) optionally substituted with        with 1, 2 or 3 substituents, each substituent being        independently OH, halo, C₁₋₃ alkoxy, C₂-C₄ alkenyl, C₂-C₄        alkynyl, —N(R^(a))(R^(b)) where R^(a) and R^(b) are        independently H, OH (R^(a) and R^(b) are not both OH), C₂₋₆        hydroxyalkyl, or C₁₋₆ alkyl or R^(a) and R^(b) together with the        nitrogen atom to which they are both linked form a 3, 4, 5 or        6-membered heterocycle;    -   —(C₀₋₃ alkyl)CO₂R^(d), wherein R^(d) is an C₁₋₆ alkyl        (preferably C₁₋₃ alkyl, more preferably methyl or ethyl)        optionally substituted with 1, 2 or 3 substituents, each        substituent being independently OH, halo, C₁₋₃ alkoxy (e.g.,        fluoroalkoxy), —N(R^(a))(R^(b)) where R^(a) and R^(b) are        independently H, OH (R^(a) and R^(b) are not both OH), C₂₋₆        hydroxyalkyl, or C₁₋₆ alkyl or R^(a) and R^(b) together with the        nitrogen atom to which they are both linked form a 3, 4, 5 or        6-membered heterocycle; or    -   —N(R^(a))(R^(b)) where R^(a) and R^(b) are independently H; OH        (R^(a) and R^(b) are not both OH); C₂₋₆ hydroxyalkyl; C₁₋₆        alkyl; or C₁₋₆ alkyl substituted with —N(R^(e))(R^(f)) where        R^(e) and R^(f) are independently H, OH (R^(e) and R^(f) are not        both OH), or C₁₋₃ alkyl; wherein optionally R^(a) and R^(b)        together, and/or R^(e) and R^(f) together, with the nitrogen        atom to which they are linked form a 3, 4, 5 or 6-membered        heterocycle;    -   —(C₀₋₃ alkyl)C(O)N(R^(a))(R^(b)) wherein R^(a) and R^(b) are        independently C₁₋₃ alkyl, C₂₋₃ hydroxyalkyl or C₁₋₃ haloalkyl;        preferably when R₉ is H, then at least one of R₈ and R₁₀ is not        H, more preferably R₉ is other than H;-   R₇ and R₁₁ are independently H, halo (preferably F or Cl, more    preferably F), C₁₋₃ alkyl (preferably CH₃), or C₁₋₄ alkoxy    (preferably OCH3); and-   W, X, Y, and Z are as defined above, provided that when W, X, Y or Z    is N there is no substituent at the N.

In another preferred embodiment of the compounds of Formula Vc,

-   R₁ is methyl or ethyl, more preferably methyl;-   R₂ is H; halo; N₃;    -   C₁₋₆ alkyl (preferably C₁₋₃ alkyl, more preferably CH₃)        optionally substituted with OH or halo (preferably F, e.g.,        monofluoro, difluoro, or trifluoro);    -   —XR_(2a) wherein X is S or O, and R_(2a) is C₁₋₆ alkyl        (preferably C₁₋₃ alkyl, more preferably CH₃) optionally        substituted with OH or halo (preferably F, e.g., monofluoro-,        difluoro-, or trifluoro-substituted);    -   CO₂R^(d), wherein R^(d) is C₁₋₃ alkyl, preferably methyl or        ethyl; or    -   —N(R^(a))(R^(b)) wherein R^(a) and R^(b) are independently H, OH        (R^(a) and R^(b) are not both OH), C₁₋₃ alkyl (preferably CH₃),        C₁₋₆ hydroxyalkyl (preferably C₂₋₃ hydroxyalkyl, more preferably        —CH₂CH₂OH), or C₁₋₆ alkyl (preferably C₁₋₃ alkyl, more        preferably CH₃) that is optionally substituted with        N(R^(e))(R^(f)) wherein R^(e) and R^(f) are independently H, OH        (R^(e) and R^(f) are not both OH), C₁₋₃ alkyl (preferably CH₃),        or C₂₋₃ hydroxyalkyl (preferably —CH₂CH2OH), and wherein        optionally R^(a) and R^(b) together may form a 3, 4, 5 or        6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and        morpholinyl);-   R₃ is H; halo; C₁₋₃ alkyl; or C₁₋₃ alkoxy;-   R₄, R₆ are independently H; halo (preferably F or Cl); N₃; C₁₋₃    alkyl (preferably CH₃); C₁₋₃ alkoxy (preferably OCH₃); or    —N(R^(a))(R^(b)) wherein R^(a) and R^(b) are independently H, OH,    C₁₋₃ alkyl, (hydroxy)C₁₋₃ alkyl, and optionally R^(a) and R^(b)    together may form a 3, 4, 5 or 6-membered heterocycle (e.g.,    piperidinyl, pyrrolidinyl, and morpholinyl), and wherein R^(a) and    R^(b) are not both OH;-   R₅ is H;-   R₇ and R₁₁ are independently H, halo (preferably F), CH₃, or OCH₃;-   R₈ and R₁₀ are independently H; halo (preferably F or Cl, more    preferably F); C₁₋₃ alkyl (preferably CH₃); C₁₋₃ alkoxy (preferably    OCH₃); and-   R₉ is selected from the group: H; OH; Cl; N₃; C₁₋₃ alkyl (preferably    methyl or ethyl) or C₁₋₃ haloalkyl (preferably monofluoromethyl,    difluoromethyl, trifluoromethyl); —OR_(9a), wherein R_(9a) is C₁₋₃    alkyl (i.e., methyl, ethyl, propyl, isopropyl) or C₁₋₃ haloalkyl    (e.g., fluoroalkyl, preferably fluoromethyl, i.e., CH₂F, CHF₂, CF₃);    —N(R^(a))(R^(b)) wherein R^(a) and R^(b) are independently H or C₁₋₃    alkyl; —(C₀₋₃ alkyl)COOR_(9b), wherein R_(9b) is C₁₋₃ alkyl    (preferably methyl or ethyl); or —(C₀₋₃ alkyl)C(O)N(R^(a))(R^(b))    wherein R^(a) and R^(b) are independently C₁₋₃ alkyl; and optionally    R₉ and one of R₈ and R₁₀ together form a 3, 4, 5, or 6-membered    heterocycle; preferably when R₉ is H, then at least one of R₈ and    R₁₀ is not H, more preferably R₉ is other than H; and-   W, X, Y, and Z are independently C or N, provided that at least one    of W, X, Y, and Z is N, wherein when W, X, Y, or Z is nitrogen, then    there is no substituent at the N.

In more preferred embodiment, compounds of the invention includecompounds of Formula Vc or pharmaceutically acceptable salts or solvatesthereof, wherein:

-   R₁ is methyl or ethyl, preferably methyl;-   R₂ is H, methyl, ethyl, Cl, F, fluoromethyl (CH₂F, CHF₂, CF₃), C₁₋₃    hydroxyalkyl (preferably CH₂OH or CH₂CH₂OH), NH₂, NH₂OH,    —NHCH₂CH₂OH, NHCH₃, N(CH₃)₂, N₃, morpholino, OCH₃, OC₂H₅, or SCH₃;-   R₃ is H, CH₃, OCH₃, F, or Cl;-   R₄ and R₆ are independently H, CH₃, NH₂, N₃, F, or Cl;-   R₅ is H;-   R₇ and R₁₁ are independently H, F, or OCH₃;-   R₈ and R₁₀ are independently H, F, Cl, or OCH₃;-   R₉ is selected from the group of consisting of H; OH; Cl; N₃; C₁₋₃    alkyl (preferably methyl or ethyl); C₁₋₃ haloalkyl (preferably    monofluoromethyl, difluoromethyl, trifluoromethyl); —OR_(9a) where    R_(9a) is C₁₋₃ alkyl (i.e., methyl, ethyl, propyl, isopropyl) or    C₁₋₃ haloalkyl (e.g., fluoroalkyl, preferably fluoromethyl, i.e.,    CH₂F, CHF₂, CF₃); —N(R^(a))(R^(b)) wherein R^(a) and R^(b) are    independently H or C₁₋₃ alkyl; and —COOR_(9b), wherein R_(9b) is    C₁₋₃ alkyl (preferably methyl or ethyl), and optionally R₉ and one    of R₈ and R₁₀ together form a 3, 4, 5, or 6-membered heterocycle;    preferably when R₉ is H, then at least one of R₈ and R₁₀ is not H,    more preferably R₉ is other than H; and-   W, X, Y and Z are as defined above, provided that when W, X, Y or Z    is N, then there is no substituent at the N. Preferably in this    embodiment, when R₉ is alkyl, R₂ not H.

In a even more preferred embodiment, compounds of the invention includecompounds of Formula Vc or pharmaceutically acceptable salts or solvatesthereof, wherein R₁ is methyl; R₂ is H, methyl, Cl, —CH₂OH, —NH₂,—NHCH₃, —NHCH₂CH₂OH, —OCH₃, —SCH₃, or —CH₂F; R₃ and R₁₂ areindependently H, methyl, —OCH₃, or Cl; R₄ is H, methyl, or NH₂; R₅ is H;R₆ and R₁₃ are independently H or methyl; R₇ and R₁₁ are independently Hor F; R₈ and R₁₀ are independently H, or F or OCH₃; and R₉ is —OCH₃,—OC₂H₅, —N(CH₃)₂, —CO₂CH₃, —OCHF₂, or N₃; and W, X, Y, and Z are asdefined above, provided that when W, X, Y, or Z is N, then there is nosubstituent at the N.

In all embodiments of the compounds of Formula Vc, it is preferred thatone of W, X, Y and Z is N, or two of W, X, Y and Z are N.

Other preferred compounds of the present invention are those representedby Formula VI:

or pharmaceutically acceptable salts or solvates thereof, wherein:

-   R₁ is methyl or ethyl, preferably methyl;-   R₅ is H or F, preferably H;-   R₂-R₄, and R₆-R₁₃ are independently H, halo, N₃, OH, thiol, nitro,    CN, NH₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆    alkylthiol, halo-C₁₋₆ alkyl, C₂₋₆ alkenyl-O—, C₂₋₆ alkynyl-O—,    hydroxy-C₁₋₆ alkyl, C₁₋₆ alkoxy-C₁₋₆ alkyl, C₁₋₆ acyl, C₁₋₆ acyloxy,    —C₁₋₆ alkyl-C(O)O—C₁₋₆ alkyl, —C(O)O—C₁₋₆ alkyl, C₁₋₆    alkyl-C(O)O—C₁₋₆ alkyl-, C₁₋₆ acylamido, —N(R^(a))(R^(b)), —C₁₋₆    alkyl-C(O)N(R^(a))(R^(b)), —C(O)N(R^(a))(R^(b)),    N(R^(a))(R^(b))—C₁₋₆ alkyl-, 3, 4, 5, or 6-membered carbocycle,    heterocycle, aryl, or heteroaryl, wherein R^(a) and R^(b) are    independently H, OH (R^(a) and R^(b) are not both OH), C₂₋₆    hydroxyalkyl, or C₁₋₆ alkyl, or R^(a) and R^(b) together with the    nitrogen atom to which they are both linked form a 3, 4, 5 or    6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and    morpholinyl); wherein any of the groups is optionally substituted    with 1-3 substituents wherein each substituent is independently    halo, N₃, OH, thiol, nitro, CN, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆    alkynyl, C₁₋₆ alkoxy, C₁₋₆ alkylthiol, C₂₋₆ alkenyl-O—, C₂₋₆    alkynyl-O—, hydroxy-C₁₋₆ alkyl, C₁₋₆ alkoxy-C₁₋₆ alkyl, C₁₋₆ acyl,    C₁₋₆ acyloxy, —C₁₋₆ alkyl-C(O)O—C₁₋₆ alkyl, —C(O)O—C₁₋₆ alkyl, C₁₋₆    alkyl-C(O)O—C₁₋₆ alkyl-, C₁₋₆ acylamido, —N(R^(a))(R^(b)), —C₁₋₆    alkyl-C(O)N(R^(a))(R^(b)), —C(O)N(R^(a))(R^(b)),    N(R^(a))(R^(b))—C₁₋₆ alkyl-, wherein R^(a) and R^(b) are    independently H, OH (R^(a) and R^(b) are not both OH), C₂₋₆    hydroxyalkyl, or C₁₋₆ alkyl or R^(a) and R^(b) together with the    nitrogen atom to which they are both linked to form a 3, 4, 5 or    6-membered heterocycle, wherein optionally any two adjacent R₇-R₁₁    groups together form a 3, 4, 5 or 6-membered carbocycle or    heterocycle; and-   B, D, Q, T, U and V are independently C or N, provided that at least    one of B and D is N, and when B, D, Q, T, U or V is N, then there is    no substituent at the N;-   wherein when Q, T, U and V are all C, then R₉ is not carboxyalkoxy    or an ester thereof (preferably R₉ is not —O(C₁₋₆ alkyl)C(O)O(C₁₋₆    alkyl); wherein when R₉ is H then at least one of R₈ and R₁₀ is not    H or halo or alkyl; and-   wherein when R₉ is alkyl, then R₂ is not aryl.

In one embodiment, compounds of the invention include compounds ofFormula VI or pharmaceutically acceptable salts or solvates thereof,wherein:

-   R₁ is methyl or ethyl, preferably methyl;-   R₅ is H or F, preferably H;-   R₂-R₄, R₆-R₁₁ are independently H, halo, N₃, OH, thiol, nitro, CN,    NH₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆    alkylthiol, halo-C₁₋₆ alkyl, C₂₋₆ alkenyl-O—, C₂₋₆ alkynyl-O—,    hydroxy-C₁₋₆ alkyl, C₁₋₆ alkoxy-C₁₋₆ alkyl, C₁₋₆ acyl, C₁₋₆ acyloxy,    —C₁₋₆ alkyl-C(O)O—C₁₋₆ alkyl, —C(O)O—C₁₋₆ alkyl, C₁₋₆    alkyl-C(O)O—C₁₋₆ alkyl-, C₁₋₆ acylamido, —N(R^(a))(R^(b)), —C₁₋₆    alkyl-C(O)N(R^(a))(R^(b)), —C(O)N(R^(a))(R^(b)),    N(R^(a))(R^(b))—C₁₋₆ alkyl-, 3, 4, 5, or 6-membered carbocycle,    heterocycle, aryl, or heteroaryl, wherein R^(a) and R^(b) are    independently H, OH (R^(a) and R^(b) are not both OH), C₂₋₆    hydroxyalkyl, or C₁₋₆ alkyl, or R^(a) and R^(b) together with the    nitrogen atom to which they are both linked to form a 3, 4, 5 or    6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and    morpholinyl); wherein any of the groups is optionally substituted    with 1-3 substituents wherein each substituent is independently    halo, N₃, OH, thiol, nitro, CN, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆    alkynyl, C₁₋₆ alkoxy, C₁₋₆ alkylthiol, C₂₋₆ alkenyl-O—, C₂₋₆    alkynyl-O—, hydroxy-C₁₋₆ alkyl, C₁₋₆ alkoxy-C₁₋₆ alkyl, C₁₋₆ acyl,    C₁₋₆ acyloxy, —C₁₋₆ alkyl-C(O)O—C₁₋₆ alkyl, —C(O)O—C₁₋₆ alkyl, C₁₋₆    alkyl-C(O)O—C₁₋₆ alkyl-, C₁₋₆ acylamido, —N(R^(a))(R^(b)), —C₁₋₆    alkyl-C(O)N(R^(a))(R^(b)), —C(O)N(R^(a))(R^(b)),    N(R^(a))(R^(b))—C₁₋₆ alkyl-, wherein R^(a) and R^(b) are    independently H, OH (R^(a) and R^(b) are not both OH), C₂₋₆    hydroxyalkyl, or C₁₋₆ alkyl or R^(a) and R^(b) together with the    nitrogen atom to which they are both linked form a 3, 4, 5 or    6-membered heterocycle, wherein optionally any two adjacent R₇-R₁₁    groups together form a 3, 4, 5 or 6-membered carbocycle or    heterocycle; exactly one of B and D is N; and-   Q, T, U and V are independently C or N, wherein at least one of Q,    T, U and V is N, and when Q, T, U or V is N there is no substituent    at the N, provided that when R₉ is H then R₂ is not optionally    substituted aryl or heteroaryl. Preferably, R₈ and R₁₀ are not both    H, or one H and the other alkyl. Preferably when R₉ is H then at    least one of R₈ and R₁₀ is not H or alkyl. More preferably, when R₉    is H then at least one of R₈ and R₁₀ is not H, alkyl, or halo.

In one embodiment, R₉ is selected from the group consisting of H, OH,Cl, N₃;

C₁₋₆ alkyl (preferably C₁₋₃ alkyl, more preferably CH₃) optionallysubstituted with 1, 2 or 3 substituents, each substituent beingindependently OH, halo, C₁₋₃ alkoxy, (halo)C₁₋₃ alkoxy, —N(R^(a))(R^(b))where R^(a) and R^(b) are independently H, OH (R^(a) and R^(b) are notboth OH), C₂₋₄ hydroxyalkyl, or C₁₋₃ alkyl or R^(a) and R^(b) togetherwith the nitrogen atom to which they are both linked to form a 3, 4, 5or 6-membered heterocycle;

—XR^(c) wherein X is S or O and R^(c) is C₁₋₆ alkyl (preferably C₁₋₃alkyl, more preferably CH₃) optionally substituted with with 1, 2 or 3substituents, each substituent being independently OH, halo, C₁₋₃alkoxy, or (halo)C₁₋₃ alkoxy;

—(C₀₋₃ alkyl)CO₂R^(d), wherein R^(d) is an C₁₋₆ alkyl (preferably C₁₋₃alkyl, more preferably methyl or ethyl) optionally substituted with 1, 2or 3 substituents, each substituent being independently OH, halo, C₁₋₃alkoxy (e.g., fluoroalkoxy), —N(R^(a))(R^(b)) where R^(a) and R^(b) areindependently H, OH (R^(a) and R^(b) are not both OH), C₂₋₄hydroxyalkyl, or C₁₋₃ alkyl or R^(a) and R^(b) together with thenitrogen atom to which they both are linked form a 3, 4, 5 or 6-memberedheterocycle;

—N(R^(a))(R^(b)) where R^(a) and R^(b) are independently H, OH (R^(a)and R^(b) are not both OH), C₂₋₄ hydroxyalkyl, C₁₋₃ alkyl, or C₁₋₃ alkylsubstituted with —N(R^(e))(R^(f)) where R^(e) and R^(f) areindependently H, OH (R^(e) and R^(f) are not both OH), or C₁₋₃ alkyl;wherein optionally R^(a) and R^(b) together with the N form a 3, 4, 5 or6-membered heterocycle, and optionally R^(e) and R^(f) together with thenitrogen atom to which they both are linked form a 3, 4, 5 or 6-memberedheterocycle; or

—(C₀₋₃ alkyl)C(O)N(R^(a))(R^(b)) where R^(a) and R^(b) are independentlyH or C₁₋₃ alkyl; and optionally R₉ and one of R₈ and R₁₀ together form a3, 4, 5, or 6-membered heterocycle; preferably R₉ is selected from thegroup outlined above except R₉ is not H and C₁₋₆alkyl.

In another embodiment, R₉ is H; OH; Cl; N₃; C₁₋₃ alkyl (preferablymethyl; C₁₋₃ haloalkyl (preferably monofluoromethyl, difluoromethyl,trifluoromethyl); —OR_(9a), wherein R_(9a) is C₁₋₄ alkyl or C₁₋₃haloalkyl (e.g., fluoroalkyl, preferably fluoromethyl, i.e., CH₂F, CHF₂,CF₃); —NH(R^(a)); —N(R^(a))(R^(b)) where R^(a) and R^(b) areindependently C₁₋₃ alkyl; or —COOR_(9b), wherein R_(9b) is C₁₋₃ alkyl(preferably methyl or ethyl); and optionally R₉ and one of R₈ and R₁₀together form a 3, 4, 5, or 6-membered heterocycle; preferably R₉ isselected from the group outlined above except R₉ is not H or C₁₋₃alkyl.

In a preferred embodiment, R₉ is N₃, —OR_(9a) wherein R_(9a) is C₁₋₃alkyl optionally substituted with 1-7 F, —N(R^(a))(R^(b)) where R^(a)and R^(b) are independently C₁₋₃ alkyl, —COOR_(9b) where R_(9b) is C₁₋₃alkyl.

In a more preferred embodiment, R₉ is —OCH₃, —OC₂H₅, —N(CH₃)₂, —CO₂CH₃,—OCHF₂, or N₃.

In the various embodiments of the compounds according to Formula VIpreferably when R₉ is H, R₈ or R₁₀ or both are independently OH; Cl; N₃;—XR_(9a), where X is O or S, and R_(9a) is C₁₋₄ alkyl or C₁₋₃ haloalkyl(e.g., fluoroalkyl, preferably fluoromethyl, i.e., CH₂F, CHF₂, CF₃);—NH(R^(a)) or —N(R^(a))(R^(b)) where R^(a) and R^(b) are independentlyC₁₋₃ alkyl; or —COOR_(9b), wherein R_(9b) is C₁₋₃ alkyl (preferablymethyl or ethyl). More preferably, when R₉ is H, R₈ or R₁₀ or both areindependently N₃, —OR_(9a), wherein R_(9a) is C₁₋₄ alkyl or C₁₋₃haloalkyl; —N(R^(a))(R^(b)) where R^(a) and R^(b) are independently C₁₋₃alkyl; or —COOR_(9b), wherein R_(9b) is C₁₋₃ alkyl (preferably methyl orethyl). Even more preferably when R₉ is H, R₈ or R₁₀ or both are C₁₋₃alkoxy or C₁₋₃ haloalkoxy.

Also preferably in the various embodiments, when R₉ is H then R₂ is notH, and preferably R₂ is halo; C₁₋₃ alkyl optionally substituted with OHor halo (preferably F, e.g., monofluoro, difluoro, or trifluoro);—XR_(2a) wherein X is S or O and R_(2a) is C₁₋₃ alkyl (preferably C₁₋₃alkyl, more preferably CH₃) optionally substituted with halo (preferablyF, e.g., monofluoro-, difluoro-, or trifluoro-substituted); or—N(R^(a))(R^(b)) wherein R^(a) and R^(b) are independently H, OH (R^(a)and R^(b) are not both OH), C₁₋₃ alkyl (preferably CH₃), C₂₋₃hydroxyalkyl. More preferably R₂ is methyl, ethyl, Cl, F, fluoromethyl(CH₂F, CHF₂, CF₃), C₁₋₃ hydroxyalkyl (preferably CH₂OH or CH₂CH₂OH),NH₂, NH₂OH, —NHCH₂CH₂OH, NHCH₃, N(CH₃)₂, N₃, morpholino, OCH₃, OC₂H₅, orSCH₃.

Also preferably, when R₉ is C₁₋₆ alkyl or C₁₋₆ haloalkyl, R₂ is not H,and preferably is methyl, ethyl, Cl, F, fluoromethyl (CH₂F, CHF₂, CF₃),C₁₋₃ hydroxyalkyl (preferably CH₂OH or CH₂CH₂OH), NH₂, NH₂OH,—NHCH₂CH₂OH, NHCH₃, N(CH₃)₂, N₃, morpholino, OCH₃, OC₂H₅, or SCH₃.

In one embodiment, R₂ is H; halo; N₃; C₁₋₆ alkyl (preferably C₁₋₃ alkyl,more preferably CH₃) optionally substituted with OH or halo (preferablyF, e.g., monofluoro, difluoro, or trifluoro); —XR_(2a) wherein X is S orO, and R_(2a) is C₁₋₆ alkyl (preferably C₁₋₃ alkyl, more preferably CH₃)optionally substituted with OH or halo (preferably F, e.g., monofluoro-,difluoro-, or trifluoro-substituted); CO₂R^(d), wherein R^(d) is C₁₋₃alkyl, preferably methyl or ethyl; or N(R^(a))(R^(b)) wherein R^(a) andR^(b) are independently H, OH (R^(a) and R^(b) are not both OH), C₁₋₃alkyl (preferably CH₃), C₁₋₆ hydroxyalkyl (preferably C₂₋₃ hydroxyalkyl,more preferably —CH₂CH₂OH), or C₁₋₆ alkyl (preferably C₁₋₃ alkyl, morepreferably CH₃) that is optionally substituted with —N(R^(e))(R^(f))wherein R^(e) and R^(f) are independently H, OH (R^(e) and R^(f) are notboth OH), C₁₋₃ alkyl (preferably CH₃), or C₂₋₃ hydroxyalkyl (preferably—CH₂CH2OH), and wherein optionally R^(a) and R^(b) together with the Nthey are both linked to may form a 3, 4, 5 or 6-membered heterocycle.

In a preferred embodiment, R₂ is H; halo; C₁₋₃ alkyl optionallysubstituted with OH or halo (preferably F, e.g., monofluoro, difluoro,or trifluoro); —XR_(2a) wherein X is S or O and R_(2a) is C₁₋₃ alkyl(preferably C₁₋₃ alkyl, more preferably CH₃) optionally substituted withhalo (preferably F, e.g., monofluoro-, difluoro-, ortrifluoro-substituted); or —N(R^(a))(R^(b)) wherein R^(a) and R^(b) areindependently H, OH (R^(a) and R^(b) are not both OH), C₁₋₃ alkyl(preferably CH₃), C₂₋₃ hydroxyalkyl.

In preferred embodiments, R₂ is H, methyl, ethyl, Cl, F, fluoromethyl(CH₂F, CHF₂, CF₃), C₁₋₃ hydroxyalkyl (preferably CH₂OH or CH₂CH₂OH),NH₂, NH₂OH, —NHCH₂CH₂OH, NHCH₃, N(CH₃)₂, N₃, morpholino, OCH₃, OC₂H₅, orSCH₃.

In more preferred embodiments, R₂ is H, methyl, Cl, —CH₂OH, —NH₂,—NHCH₃, —NHCH₂CH₂OH, —OCH₃, —SCH₃, or —CH₂F.

In all embodiments of the compound of Formula VI, it is preferred thatone or two of Q, T, U and V are N. For example Q and V are N and T and Uare C.

In one embodiment, compounds of the invention include compounds ofFormula VI or pharmaceutically acceptable salts or solvates thereof,wherein:

-   R₁ is methyl or ethyl, preferably methyl;-   R₂ is H; halo; N₃;    -   C₁₋₆ alkyl (preferably C₁₋₃ alkyl, more preferably CH₃)        optionally substituted with OH or halo (preferably F, e.g.,        monofluoro, difluoro, or trifluoro);    -   —XR_(2a) wherein X is S or O, and R_(2a) is C₁₋₆ alkyl        (preferably C₁₋₃ alkyl, more preferably CH₃) optionally        substituted with OH or halo (preferably F, e.g., monofluoro-,        difluoro-, or trifluoro-substituted);    -   —CO₂R^(d), wherein R^(d) is C₁₋₃ alkyl, preferably methyl or        ethyl; or    -   —N(R^(a))(R^(b)) wherein R^(a) and R^(b) are independently H, OH        (R^(a) and R^(b) are not both OH), C₁₋₃ alkyl (preferably CH₃),        C₁₋₆ hydroxyalkyl (preferably C₂₋₃ hydroxyalkyl, more preferably        —CH₂CH₂OH), or C₁₋₆ alkyl (preferably C₁₋₃ alkyl, more        preferably CH₃) that is optionally substituted with        N(R^(e))(R^(f)) wherein R^(e) and R^(f) are independently H, OH        (R^(e) and R^(f) are not both OH), C₁₋₃ alkyl (preferably CH₃),        or C₂₋₃ hydroxyalkyl (preferably —CH₂CH2OH), and wherein        optionally R^(a) and R^(b) together with the N they are both        linked to may form a 3, 4, 5 or 6-membered heterocycle (e.g.,        piperidinyl, pyrrolidinyl, and morpholinyl);-   R₃ is H; halo; C₁₋₃ alkyl; or C₁₋₃ alkoxy;-   R₄ and R₆ are independently H; halo (preferably F or Cl); N₃, C₁₋₆    alkyl (preferably C₁₋₃, more preferably CH₃); C₁₋₃ alkoxy    (preferably OCH₃); or —N(R_(2b))(R_(2c)) wherein R_(2b) and R_(2c)    are independently H, OH, C₁₋₆ alkyl (preferably C₁₋₃ alkyl, more    preferably CH₃), C₁₋₆ hydroxyalkyl (preferably C₂₋₃ hydroxyalkyl,    more preferably —CH₂CH2OH), or C₁₋₆ alkyl (preferably C₁₋₃ alkyl,    more preferably CH₃) that is optionally substituted with    —N(R_(2d))(R_(2e)) wherein R_(2d) and R_(2e) are independently H,    OH, C₁₋₃ alkyl (preferably CH₃) or C₂₋₃ hydroxyalkyl (preferably    —CH₂CH2OH), wherein R_(2b) and R_(2c) together with the N they are    both linked to may form a 3, 4, 5 or 6-membered heterocycle (e.g.,    piperidinyl, pyrrolidinyl, and morpholinyl), and wherein R_(2b) and    R_(2c) are not both OH, R_(2d) and R_(2e) are not both OH;-   R₅ is H or F, preferably H;-   R₇ and R₁₁ are independently H; halo (preferably F or Cl, more    preferably F); CH₃; or OCH₃;-   R₈ and R₁₀ are independently H; halo (preferably F or Cl, more    preferably Cl); OH; N₃; C₁₋₃ alkyl (preferably CH₃); C₁₋₃ alkoxy    (preferably OCH₃); C₁₋₃ haloalkyl (preferably monofluoromethyl,    difluoromethyl, trifluoromethyl); —XR_(9a), where X is O or S, and    R_(9a) is C₁₋₄ alkyl or C₁₋₃ haloalkyl (e.g., fluoroalkyl,    preferably fluoromethyl, i.e., CH₂F, CHF₂, CF₃); —NH(R^(a)) or    N(R^(a))(R^(b)) where R^(a) and R^(b) are independently C₁₋₃ alkyl;    or —COOR_(9b), wherein R_(9b) is C₁₋₃ alkyl (preferably methyl or    ethyl);-   R₉ is selected from the group consisting of H, OH, Cl, N₃;

C₁₋₆ alkyl (preferably C₁₋₃ alkyl, more preferably CH₃) optionallysubstituted with 1, 2 or 3 substituents, each substituent beingindependently OH, halo, C₁₋₃ alkoxy, (halo)C₁₋₃ alkoxy, —N(R^(a))(R^(b))where R^(a) and R^(b) are independently H, OH (R^(a) and R^(b) are notboth OH), C₂₋₄ hydroxyalkyl, or C₁₋₃ alkyl or R^(a) and R^(b) togetherwith the nitrogen atom to which they are both linked form a 3, 4, 5 or6-membered heterocycle;

—XR^(c) wherein X is S or O and R^(c) is C₁₋₆ alkyl (preferably C₁₋₃alkyl, more preferably CH₃) optionally substituted with with 1, 2 or 3substituents, each substituent being independently OH, halo, C₁₋₃alkoxy, or (halo)C₁₋₃ alkoxy;

—(C₀₋₃ alkyl)CO₂R^(d), wherein R^(d) is an C₁₋₆ alkyl (preferably C₁₋₃alkyl, more preferably methyl or ethyl) optionally substituted with 1, 2or 3 substituents, each substituent being independently OH, halo, C₁₋₃alkoxy (e.g., fluoroalkoxy), N(R^(a))(R^(b)) where R^(a) and R^(b) areindependently H, OH (R^(a) and R^(b) are not both OH), C₂₋₄hydroxyalkyl, or C₁₋₃ alkyl or R^(a) and R^(b) together with thenitrogen atom to which they both are linked form a 3, 4, 5 or 6-memberedheterocycle;

—N(R^(a))(R^(b)) where R^(a) and R^(b) are independently H, OH (R^(a)and R^(b) are not both OH), C₂₋₄ hydroxyalkyl, C₁₋₃ alkyl, or C₁₋₃ alkylsubstituted with —N(R^(e))(R^(f)) where R^(e) and R^(f) areindependently H, OH (R^(e) and R^(f) are not both OH), or C₁₋₃ alkyl;wherein optionally R^(a) and R^(b) together with the N form a 3, 4, 5 or6-membered heterocycle, and optionally R^(e) and R^(f) together with thenitrogen atom to which they both are linked form a 3, 4, 5 or 6-memberedheterocycle; or

—(C₀₋₃ alkyl)C(O)N(R^(a))(R^(b)) where R^(a) and R^(b) are independentlyH or C₁₋₃ alkyl; and optionally R₉ and one of R₈ and R₁₀ together form a3, 4, 5, or 6-membered heterocycle; provided that when R₉ is H, at leastone of R₈ and R₁₀ is not hydrogen or alkyl;

-   exactly one of B and D is N; and-   Q, T, U and V are independently C or N, provided that at least one    of Q, T, U and V is N, wherein when Q, T, U or V is N, then there is    no substituent at the N. In some specific embodiments, one or two of    Q, T, U and V are N.

Preferably when R₉ is H, R₈ or R₁₀ or both are independently OH; Cl; N₃,—XR_(9a), where X is O or S, and R_(9a) is C₁₋₄ alkyl or C₁₋₃ haloalkyl(e.g., fluoroalkyl, preferably fluoromethyl, i.e., CH₂F, CHF₂, CF₃);—NH(R^(a)) or —N(R^(a))(R^(b)) where R^(a) and R^(b) are independentlyC₁₋₃ alkyl; or —COOR_(9b), wherein R_(9b) is C₁₋₃ alkyl (preferablymethyl or ethyl). More preferably, when R₉ is H, R₈ or R₁₀ or both areindependently N₃, —OR_(9a), wherein R_(9a) is C₁₋₄ alkyl or C₁₋₃haloalkyl, or —N(R^(a))(R^(b)) where R^(a) and R^(b) are independentlyC₁₋₃ alkyl; or —COOR_(9b), wherein R_(9b) is C₁₋₃ alkyl (preferablymethyl or ethyl). Even more preferably when R₉ is H, R₈ or R₁₀ or bothare C₁₋₃ alkoxy or C₁₋₃ haloalkoxy.

Also preferably, when R₉ is C₁₋₆ alkyl or C₁₋₆ haloalkyl, R₂ is methyl,ethyl, Cl, F, fluoromethyl (CH₂F, CHF₂, CF₃), C₁₋₃ hydroxyalkyl(preferably CH₂OH or CH₂CH₂OH), NH₂, NH₂OH, —NHCH₂CH₂OH, NHCH, N(CH₃)₂,N₃, morpholino, OCH₃, OC₂H₅, or SCH₃.

In another preferred embodiment, compounds of the invention includecompounds of Formula VI or pharmaceutically acceptable salts or solvatesthereof, wherein:

-   R₁ is methyl or ethyl, and preferably methyl;-   R₂ is H; halo; N₃;    -   C₁₋₆ alkyl (preferably C₁₋₃ alkyl, more preferably CH₃)        optionally substituted with OH or halo (preferably F, e.g.,        monofluoro, difluoro, or trifluoro);    -   —XR_(2a) wherein X is S or 0, and R_(2a) is C₁₋₆ alkyl        (preferably C₁₋₃ alkyl, more preferably CH₃) optionally        substituted with OH or halo (preferably F, e.g., monofluoro-,        difluoro-, or trifluoro-substituted);    -   —CO₂—R_(2f), wherein R_(2f) is C₁₋₆ alkyl (preferably C₁₋₃        alkyl, more preferably methyl or ethyl); or    -   —N(R_(2b))(R_(2c)) wherein R_(2b) and R_(2c) are independently        H, OH, C₁₋₆ alkyl (preferably C₁₋₃ alkyl, more preferably CH₃),        C₁₋₆ hydroxyalkyl (preferably C₂₋₃ hydroxyalkyl, more preferably        —CH₂CH2OH), or C₁₋₆ alkyl (preferably C₁₋₃ alkyl, more        preferably CH₃) that is optionally substituted with        —N(R_(2d))(R_(2e)) wherein R_(2d) and R_(2e) are independently        H, OH, C₁₋₃ alkyl (preferably CH₃), or C₂₋₃ hydroxyalkyl        (preferably CH₂CH₂OH), and wherein optionally R_(2b) and R_(2c)        together with the N they are both linked to may form a 3, 4, 5        or 6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and        morpholinyl), and wherein R_(2b) and R_(2c) are not both OH,        R_(2d) and R_(2e) are not both OH;-   R₃ is H; halo; C₁₋₃ alkyl; or C₁₋₃ alkoxy;-   R₄ and R₆ are independently H; halo (preferably F or CO; N_(3;) C₁₋₃    alkyl (preferably CH₃); C₁₋₃ alkoxy (preferably OCH₃); or    —N(R_(2b))(R_(2c)) wherein R_(2b) and R_(2e) are independently H,    OH, CH₃, or ethyl, and optionally R_(2b) and R_(2c) together with    the N they are both linked to may form a 3, 4, 5 or 6-membered    heterocycle (e.g., piperidinyl, pyrrolidinyl, and morpholinyl), and    wherein R_(2b) and R_(2c) are not both OH;-   R₅ is H;-   R₇ and R₁₁ are independently H, halo (preferably F), CH₃, or OCH₃;-   R₈ and R₁₀ are independently H; halo (preferably F or Cl, more    preferably F); C₁₋₃ alkyl (preferably CH₃); C₁₋₃ alkoxy (preferably    OCH₃); and-   R₉ is selected from the group:    -   hydrogen; hydroxy; Cl; N₃;    -   C₁₋₃ alkyl (preferably methyl or ethyl) or C₁₋₃ haloalkyl        (preferably monofluoromethyl, difluoromethyl, trifluoromethyl);    -   —OR_(9a), wherein R_(9a) is C₁₋₃ alkyl (i.e., methyl, ethyl,        propyl, isopropyl) or C₁₋₃ haloalkyl (e.g., fluoroalkyl,        preferably fluoromethyl, i.e., CH₂F, CHF₂, CF₃);    -   —N(Ra)(Rb),wherein Ra and Rb are independently H, C₁₋₃ alkyl, or        haloC₁₋₃alkyl; or    -   —COOR_(9b), wherein R_(9b) is C₁₋₃ alkyl (preferably methyl or        ethyl); and optionally R₉ and one of R_(g) and R₁₀ together form        a 3, 4, 5, or 6-membered carbocycle or heterocycle;    -   exactly one of B and D is N; and    -   Q, T, U and V are independently C or N, wherein at least one of        Q, T, U and V are N, wherein when Q, T, U or V is N, then the        there is no sub stituent at the N; with the proviso that when R₉        is H then R₈ and R₁₀ are not both H or one H and the other        alkyl. Preferably when R₉ is H then at least one of R₈ or R₁₀ is        not H or alkyl. More preferably when R₉ is H then at least one        of R₈ or R₁₀ is not H, alkyl, or halo.

In some specific embodiments, one or two of Q, T, U and V are N.

Preferably in this embodiment, when R₉ is H, R₈ or R₁₀ or both areindependently OH; Cl; N₃; C₁₋₃ haloalkyl (preferably monofluoromethyl,difluoromethyl, trifluoromethyl); —XR_(9a), where X is O or S, andR_(9a) is C₁₋₄ alkyl or C₁₋₃ haloalkyl (e.g., fluoroalkyl, preferablyfluoromethyl, i.e., CH₂F, CHF₂, CF₃); —NH(R^(a)) or —N(R^(a))(R^(b))where R^(a) and R^(b) are independently C₁₋₃ alkyl; or —COOR_(9b),wherein R_(9b) is C₁₋₃ alkyl (preferably methyl or ethyl). Morepreferably, when R₉ is H, R₈ or R₁₀ or both are independently N₃,—OR_(9a), wherein R_(9a) is C₁₋₄ alkyl or C₁₋₃ haloalkyl, or—N(R^(a))(R^(b)) where R^(a) and R^(b) are independently C₁₋₃ alkyl; or—COOR_(9b), wherein R_(9b) is C₁₋₃ alkyl (preferably methyl or ethyl).Even more preferably when R₉ is H, R₈ or R₁₀ or both are C₁₋₃ alkoxy orC₁₋₃ halo alkoxy.

Also preferably, when R₉ is C₁₋₆ alkyl or C₁₋₆ haloalkyl, R₂ is not Hand preferably R₂ is halo; C₁₋₃ alkyl optionally substituted with OH orhalo (preferably F, e.g., monofluoro, difluoro, or trifluoro); —XR_(2a)wherein X is S or O and R_(2a) is C₁₋₃ alkyl (preferably C₁₋₃ alkyl,more preferably CH₃) optionally substituted with halo (preferably F,e.g., monofluoro-, difluoro-, or trifluoro-substituted); or—N(R^(a))(R^(b)) wherein R^(a) and R^(b) are independently H, OH (R^(a)and R^(b) are not both OH), C₁₋₃ alkyl (preferably CH₃), C₂₋₃hydroxyalkyl. More preferably R₂ is methyl, ethyl, Cl, F, fluoromethyl(CH₂F, CHF₂, CF₃), C₁₋₃ hydroxyalkyl (preferably CH₂OH or CH₂CH₂OH),NH₂, NH₂OH, —NHCH₂CH₂OH, NHCH, N(CH₃)₂, N₃, morpholino, OCH₃, OC₂H₅, orSCH₃.

Also preferably, in this embodiment, when R₉ is H, R₈ or R₁₀ or both areOCH₃ and preferably R₇ and R₁₁ are H, and also preferably R₂ is nothydrogen and preferably R₂ is methyl or chloro. Also preferably in thisembodiment, when R₉ is alkyl or haloalkyl or chloro, R₂ is not hydrogenand preferably R₂ is methyl or chloro.

In another preferred embodiment, compounds of the invention includecompounds of Formula VI or pharmaceutically acceptable salts or solvatesthereof, wherein:

-   R₁ is methyl or ethyl, preferably methyl;-   R₂ is H, methyl, ethyl, Cl, F, fluoromethyl (CH₂F, CHF₂, CF₃), C₁₋₃    hydroxyalkyl (preferably CH₂OH or CH₂CH₂OH), NH₂, NH₂OH,    —NHCH₂CH₂OH, NHCH₃, N(CH₃)₂, N₃, morpholino, OCH₃, OC₂H₅, or SCH₃;    R₃ is H, CH₃, OCH₃, F, or Cl; R₄ and R₆ are independently H, CH₃,    NH₂, N₃, F, or Cl; R₅ is H; R₇ and R₁₁ are independently H, F, or    OCH₃; R₈ and R₁₀ are independently H, F, Cl, or OCH₃; and-   R₉ is selected from the group:

hydrogen; hydroxy; Cl;

-   -   C₁₋₃ alkyl (preferably methyl or ethyl) or C₁₋₃ haloalkyl        (preferably monofluoromethyl, difluoromethyl, trifluoromethyl);    -   —OR_(9a), wherein R_(9a) is C₁₋₃ alkyl (i.e., methyl, ethyl,        propyl, isopropyl) or C₁₋₃ haloalkyl (e.g., fluoroalkyl,        preferably fluoromethyl, i.e., CH₂F, CHF₂, CF₃);    -   C₁₋₃ alkyl substituted amino (preferably —NHCH₃ or —N(CH₃)₂);    -   —N₃; or    -   —COOR_(9b), wherein R_(9b) is C₁₋₃ alkyl (preferably methyl or        ethyl), and optionally R₈ and R₉ together form a 3, 4, 5, or        6-membered carbocycle or heterocycle;    -   exactly one of B and D is N; and        Q, T, U and V are independently C or N, and at least one of Q,        T, U and V is N, wherein when Q, T, U or V is N, then there is        no substituent at the N. In some specific embodiments, one or        two of Q, T, U and V are nitrogen.

Preferably in this embodiment, when R₉ is H, R₈ or R₁₀ or both areindependently OH; Cl; N₃; C₁₋₃ haloalkyl (preferably monofluoromethyl,difluoromethyl, trifluoromethyl); —XR_(9a), where X is O or S, andR_(9a) is C₁₋₄ alkyl or C₁₋₃ haloalkyl (e.g., fluoroalkyl, preferablyfluoromethyl, i.e., CH₂F, CHF₂, CF₃); —NH(R^(a)) or —N(R^(a))(R^(b))where R^(a) and R^(b) are independently C₁₋₃ alkyl; or —COOR_(9b),wherein R_(9b) is C₁₋₃ alkyl (preferably methyl or ethyl). Morepreferably, when R₉ is H, R₈ or R₁₀ or both are independently N₃,—OR_(9a), wherein R_(9a) is C₁₋₄ alkyl or C₁₋₃ haloalkyl, or—N(R^(a))(R^(b)) where R^(a) and R^(b) are independently C₁₋₃ alkyl; or—COOR_(9b), wherein R_(9b) is C₁₋₃ alkyl (preferably methyl or ethyl).Even more preferably when R₉ is H, R₈ or R₁₀ or both are C₁₋₃ alkoxy orC₁₋₃ halo alkoxy.

Also preferably, when R₉ is C₁₋₆ alkyl or C₁₋₆ haloalkyl, R₂ is not Hand preferably R₂ is methyl, ethyl, Cl, F, fluoromethyl (CH₂F, CHF₂,CF₃), C₁₋₃ hydroxyalkyl (preferably CH₂OH or CH₂CH₂OH), NH₂, NH₂OH,—NHCH₂CH₂OH, NHCH₃, N(CH₃)₂, N₃, morpholino, OCH₃, OC₂H₅, or SCH₃.

Also preferably, in this embodiment, when R₉ is H, R₈ or R₁₀ or both areOCH₃ and preferably R₇ and R₁₁ are H, and also preferably R₂ is nothydrogen and preferably R₂ is methyl or chloro. Also preferably in thisembodiment, when R₉ is alkyl or haloalkyl or chloro, R₂ is not hydrogenand preferably R₂ is methyl or chloro.

In another preferred embodiment, compounds of the invention includecompounds of Formula VI or pharmaceutically acceptable salts or solvatesthereof, wherein:

-   R₁ is methyl;-   R₂ is H, methyl, ethyl, Cl, F, fluoromethyl (CH₂F, CHF₂, CF₃),    CH₂OH, NH₂, NHCH₃, N(CH₃)₂, —NHCH₂CH₂OH, OCH₃, or SCH₃; R₃ is H,    CH₃, OCH₃, F, or Cl; R₄ and R₆ are independently H, CH₃, NH₂, F, or    Cl; R₅ is H; R₇ and R₁₁ are independently H, F, or OCH₃; R₈ and R₁₀    are independently H, F, Cl, or OCH₃; and-   R₉ is selected from the group:-   —OR_(9a), wherein R_(9a) is selected from the group of methyl,    ethyl, fluoromethyl (e.g., CH₂F, CHF₂, CF₃), and fluoroethyl;    -   —NHCH₃;    -   —N(CH₃)₂;    -   —N₃; and    -   —COOR_(9b), wherein R_(9b) is H or methyl or ethyl;-   exactly one of B and D is N; and-   Q, T, U and V are independently C or N, and at least one of Q, T, U    and V is N, wherein when Q, T, U or V is N, then there is no    substituent at the N. In some specific embodiments, one or two of Q,    T, U and V are nitrogen.

In a more preferred embodiment, compounds of the invention includecompounds of Formula VI or pharmaceutically acceptable salts or solvatesthereof, wherein:

-   R₁ is CH₃;-   R₂ is H, methyl, Cl, —CH₂OH, —NH₂, —NHCH₃, —NHCH₂CH₂OH, —OCH₃,    —SCH₃, or —CH₂F;-   R₃ is H, —CH₃, —OCH₃, or Cl;-   R₄ is H, CH₃, or NH₂;-   R₅ is H;-   R₆ is H, or CH₃;-   R₇ and R₁₁ are independently H, or F;-   R₈ and R₁₀ are independently H, or F or OCH₃;-   R₉ is —OCH₃ or —OC₂H₅, —N(CH₃)₂, —CO₂CH₃, —OCHF₂, or N₃;-   exactly one of B and D is N; and-   Q, T, U and V are independently C or N, and at least one of Q, T, U    and V is N, wherein when Q, T, U or V is N, then there is no    substituent at the N. In some specific embodiments, one or two of Q,    T, U and V are nitrogen.

In a more preferred embodiment, the present invention provides compoundsof Formula VI or pharmaceutically acceptable salts or solvates thereof,wherein R₁ is CH₃; R₂ is Cl, methyl, or CH₂F; R₃ is H, CH₃, F, or Cl;R₄, R₅ and R₆ are H; R₇, R_(g), R₁₀ and R₁₁ are independently H or F; R₉is —OCH₃ or —N(CH₃)₂; and Q, T, U and V are independently C or N, and atleast one of Q, T, U and V is N, wherein when Q, T, U or V is N, thenthere is no substituent at the N. In some specific embodiments, one ortwo of Q, T, U and V are nitrogen.

In another embodiment, compounds of the invention include compounds ofFormula VI or pharmaceutically acceptable salts or solvates thereof,wherein:

-   R₁ is methyl or ethyl, preferably methyl;-   R₅ is H or F, preferably H; and-   R₂—R₄, R₆—R₁₁ are independently H, halo, N₃, OH, thiol, nitro, CN,    NH₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆    alkylthiol, halo-C₁₋₆ alkyl, C₂₋₆ alkenyl-O—, C₂₋₆ alkynyl-O—,    hydroxy-C₁₋₆ alkyl, C₁₋₆ alkoxy-C₁₋₆ alkyl, C₁₋₆ acyl, C₁₋₆ acyloxy,    —C₁₋₆ alkyl-C(O)O—C₁₋₆ alkyl, —C(O)O—C₁₋₆ alkyl, C₁₋₆    alkyl-C(O)O—C₁₋₆ alkyl-, C₁₋₆ acylamido, —N(R^(a))(R^(b)), —C₁₋₆    alkyl-C(O)N(R^(a))(R^(b)), —C(O)N(R^(a))(R^(b)),    N(R^(a))(R^(b))—C₁₋₆ alkyl-, 3, 4, 5, or 6-membered carbocycle,    heterocycle, aryl, or heteroaryl, wherein R^(a) and R^(b) are    independently H, OH (R^(a) and R^(b) are not both OH), C₂₋₆    hydroxyalkyl, or C₁₋₆ alkyl, or R^(a) and R^(b) together with the    nitrogen atom to which they are both linked form a 3, 4, 5 or    6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and    morpholinyl); wherein any of the groups is optionally substituted    with 1-3 substituents wherein each substituent is independently    halo, N₃, OH, thiol, nitro, CN, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆    alkynyl, C₁₋₆ alkoxy, C₁₋₆ alkylthiol, C₂₋₆ alkenyl-O—, C₂₋₆    alkynyl-O—, hydroxy-C₁₋₆ alkyl, C₁₋₆ alkoxy-C₁₋₆ alkyl, C₁₋₆ acyl,    C₁₋₆ acyloxy, C₁₋₆ alkyl-C(O)O—C₁₋₆ alkyl, C₁₋₆ acylamido,    —N(R^(a))(R^(b)), —C₁₋₆ alkyl-C(O)N(R^(a))(R^(b)),    —C(O)N(R^(a))(R^(b)), N(R^(a))(R^(b))—C₁₋₆ alkyl-, wherein R^(a) and    R^(b) are independently H, OH (R^(a) and R^(b) are not both OH),    C₂₋₆ hydroxyalkyl, or C₁₋₆ alkyl or R^(a) and R^(b) together with    the nitrogen atom to which they are both linked form a 3, 4, 5 or    6-membered heterocycle, wherein optionally any two adjacent R₇-R₁₁    groups together form a 3, 4, 5 or 6-membered carbocycle or    heterocycle;-   exactly one of B and D is N provided that when B or D is N there is    no substituent at the N; and-   all of Q, T, U, and V are C;-   provided that: (1) when R₉ is H then R₈ and R₁₀ are not both H or    one H and the other halo; and (2) when R₉ is alkyl then R₂ is not    optionally substituted aryl or heteroaryl. Preferably when R₉ is H    then R₈ and R₁₀ are not both H or one H and the other halo or alkyl    or haloalkyl.

In one embodiment, R₉ is selected from the group consisting of H, Cl,N₃,

C₁₋₆ alkyl (preferably C₁₋₃ alkyl, more preferably CH₃) optionallysubstituted with 1, 2 or 3 substituents, each substituent beingindependently OH, halo, C₁₋₃ alkoxy, (halo)C₁₋₃ alkoxy, —N(R^(a))(R^(b))where R^(a) and R^(b) are independently H, OH (R^(a) and R^(b) are notboth OH), C₂₋₄ hydroxyalkyl, or C₁₋₃ alkyl or R^(a) and R^(b) togetherwith the nitrogen atom to which they are both linked form a 3, 4, 5 or6-membered heterocycle;

—XR^(c) wherein X is S or O and R^(c) is C₁₋₆ alkyl (preferably C₁₋₃alkyl, more preferably CH₃) optionally substituted with with 1, 2 or 3substituents, each substituent being independently OH, halo, C₁₋₃alkoxy, or (halo)C₁₋₃ alkoxy;

—(C₀₋₃ alkyl)CO₂R^(d), wherein R^(d) is an C₁₋₆ alkyl, preferably C₁₋₃alkyl;

—N(R^(a))(R^(b)) where R^(a) and R^(b) are independently H, OH (R^(a)and R^(b) are not both OH), C₂₋₄ hydroxyalkyl, C₁₋₃ alkyl, or—N(R^(e))(R^(f)) where R^(e) and R^(f) are independently H, OH (R^(e)and R^(f) are not both OH), or C₁₋₃ alkyl; wherein optionally R^(a) andR^(b) together with the N form a 3, 4, 5 or 6-membered heterocycle, andoptionally R^(e) and R^(f) together with the nitrogen atom to which theyboth are linked form a 3, 4, 5 or 6-membered heterocycle; or

—(C₀₋₃ alkyl)C(O)N(R^(a))(R^(b)) where R^(a) and R^(b) are independentlyH or C₁₋₃ alkyl; and optionally R₉ and one of R₈ and R₁₀ together form a3, 4, 5, or 6-membered heterocycle. Preferably R₉ is selected from suchgroups except R₉ is not H or chloro.

In another embodiment, R₉ is H; OH; Cl; N₃; C₁₋₃ alkyl (preferablymethyl; C₁₋₃ haloalkyl (preferably monofluoromethyl, difluoromethyl,trifluoromethyl); —OR_(9a), wherein R_(9a) is C₁₋₄ alkyl or C₁₋₃haloalkyl (e.g., fluoroalkyl, preferably fluoromethyl, i.e., CH₂F, CHF₂,CF₃); —NH(R^(a)) or —N(R^(a))(R^(b)) where R^(a) and R^(b) areindependently C₁₋₃ alkyl; or —COOR_(9b), wherein R_(9b) is C₁₋₃ alkyl(preferably methyl or ethyl); and optionally R₉ and one of R₈ and R₁₀together form a 3, 4, 5, or 6-membered heterocycle. Preferably R₉ isselected from such groups except R₉ is not H or chloro.

In a preferred embodiment, R₉ is N₃; —OR_(9a), wherein R_(9a) is C₁₋₃alkyl optionally substituted with 1-7 F; —N(R^(a))(R^(b)) where R^(a)and R^(b) are independently C₁₋₃ alkyl; or —COOR_(9b) where R_(9b) isC₁₋₃ alkyl.

In more preferred embodiment, R₉ is —OCH₃, —OC₂H₅, —N(CH₃)₂, —CO₂CH₃,—OCHF₂, or N₃.

Preferably when R₉ is H, R₈ or R₁₀ or both are independently OH; N₃;—XR_(9a), where X is O or S, and R_(9a) is C₁₋₄ alkyl or C₁₋₃ haloalkyl(e.g., fluoroalkyl, preferably fluoromethyl, i.e., CH₂F, CHF₂, CF₃);—NH(R^(a)) or —N(R^(a))(R^(b)) where R^(a) and R^(b) are independentlyC₁₋₃ alkyl; or —COOR_(9b), wherein R_(9b) is C₁₋₃ alkyl (preferablymethyl or ethyl). More preferably, when R₉ is H, R₈ or R₁₀ or both areindependently N₃, —OR_(9a), wherein R_(9a) is C₁₋₄ alkyl or C₁₋₃haloalkyl, or —N(R^(a))(R^(b)) where R^(a) and R^(b) are independentlyC₁₋₃ alkyl; or —COOR_(9b), wherein R_(9b) is C₁₋₃ alkyl (preferablymethyl or ethyl). Even more preferably when R₉ is H, R₈ or R₁₀ or bothare C₁₋₃ alkoxy or C₁₋₃ halo alkoxy.

Also preferably in the various embodiments, when R₉ is H, R₈ and R10 arenot H or one H and the other halo, and R2 is not H, and preferably R₂ isis halo; N₃, C₁₋₃ alkyl optionally substituted with OH or halo(preferably F, e.g., monofluoro, difluoro, or trifluoro); —XR_(2a)wherein X is S or O and R_(2a) is C₁₋₃ alkyl (more preferably CH₃)optionally substituted with halo (preferably F, e.g., monofluoro-,difluoro-, or trifluoro-substituted); or —N(R^(a))(R^(b)) wherein R^(a)and R^(b) are independently H, OH (R^(a) and R^(b) are not both OH),C₁₋₃ alkyl (preferably CH₃), C₂₋₃ hydroxyalkyl. More preferably R₂ ismethyl, ethyl, Cl, F, fluoromethyl (CH₂F, CHF₂, CF₃), C₁₋₃ hydroxyalkyl(preferably CH₂OH or CH₂CH₂OH), NH₂, NH₂OH, —NHCH₂CH₂OH, NHCH₃, N(CH₃)₂,N₃, morpholino, OCH₃, OC₂H₅, or SCH₃.

Also preferably, when R₆ is C₁₋₆ alkyl, halo, or C₁₋₆ haloalkyl, R₂ isnot H, and preferably R₂ is halo; N₃, C₁₋₃ alkyl optionally substitutedwith OH or halo (preferably F, e.g., monofluoro, difluoro, ortrifluoro); —XR_(2a) wherein X is S or O and R_(2a) is C₁₋₃ alkyl (morepreferably CH₃) optionally substituted with halo (preferably F, e.g.,monofluoro-, difluoro-, or trifluoro-substituted); or —N(R^(a))(R^(b))wherein R^(a) and R^(b) are independently H, OH (R^(a) and R^(b) are notboth OH), C₁₋₃ alkyl (preferably CH₃), C₂₋₃ hydroxyalkyl. Morepreferably R₂ is methyl, ethyl, Cl, F, fluoromethyl (CH₂F, CHF₂, CF₃),C₁₋₃ hydroxyalkyl (preferably CH₂OH or CH₂CH₂OH), NH₂, NH₂OH,—NHCH₂CH₂OH, NHCH₃, N(CH₃)₂, N₃, morpholino, OCH₃, OC₂H₅, or SCH₃.

In one embodiment, R₂ is H; halo; N₃; C₁₋₆ alkyl (preferably C₁₋₃ alkyl,more preferably CH₃) optionally substituted with OH or halo (preferablyF, e.g., monofluoro, difluoro, or trifluoro); —XR_(2a) wherein X is S orO, and R_(2a) is C₁₋₆ alkyl (preferably C₁₋₃ alkyl, more preferably CH₃)optionally substituted with OH or halo (preferably F, e.g., monofluoro-,difluoro-, or trifluoro-substituted); —CO₂R^(d), wherein R^(d) is C₁₋₃alkyl, preferably methyl or ethyl; or —N(R^(a))(R^(b)) wherein R^(a) andR^(b) are independently H, OH (R^(a) and R^(b) are not both OH), C₁₋₃alkyl (preferably CH₃), C₁₋₆ hydroxyalkyl (preferably C₂₋₃ hydroxyalkyl,more preferably —CH₂CH₂OH), or C₁₋₆ alkyl (preferably C₁₋₃ alkyl, morepreferably CH₃) that is optionally substituted with —N(R^(e))(R^(f))wherein R^(e) and R^(f) are independently H, OH (R^(e) and R^(f) are notboth OH), C₁₋₃ alkyl (preferably CH₃), or C₂₋₃ hydroxyalkyl (preferably—CH₂CH2OH), and wherein optionally R^(a) and R^(b) together with thenitrogen they both are linked to may form a 3, 4, 5 or 6-memberedheterocycle.

In a preferred embodiment, R₂ is H; halo; C₁₋₃ alkyl optionallysubstituted with OH or halo (preferably F, e.g., monofluoro, difluoro,or trifluoro); —XR_(2a) wherein X is S or O and R_(2a) is C₁₋₃ alkyl(preferably C₁₋₃ alkyl, more preferably CH₃) optionally substituted withhalo (preferably F, e.g., monofluoro-, difluoro-, ortrifluoro-substituted); or —N(R^(a))(R^(b)) wherein R^(a) and R^(b) areindependently H, OH (R^(a) and R^(b) are not both OH), C₁₋₃ alkyl(preferably CH₃), C₂₋₃ hydroxyalkyl.

In preferred embodiments, R₂ is H, methyl, ethyl, Cl, F, fluoromethyl(CH₂F, CHF₂, CF₃), C₁₋₃ hydroxyalkyl (preferably CH₂OH or CH₂CH₂OH),NH₂, NH₂OH, —NHCH₂CH₂OH, NHCH₃, N(CH₃)₂, N₃, morpholino, OCH₃, OC₂H₅, orSCH₃.

In more preferred embodiments, R₂ is H, methyl, Cl, —CH₂OH, —NH₂,—NHCH₃, —NHCH₂CH₂OH, —OCH₃, —SCH₃, or —CH₂F.

In one embodiment, compounds of the invention include compounds ofFormula VI or pharmaceutically acceptable salts or solvates thereof,wherein:

-   R₁ is methyl or ethyl, preferably methyl;-   R₂ is H; halo; N₃;    -   C₁₋₆ alkyl (preferably C₁₋₃ alkyl, more preferably CH₃)        optionally substituted with OH or halo (preferably F, e.g.,        monofluoro, difluoro, or trifluoro);    -   —XR_(2a) wherein X is S or O, and R_(2a) is C₁₋₆ alkyl        (preferably C₁₋₃ alkyl, more preferably CH₃) optionally        substituted with OH or halo (preferably F, e.g., monofluoro-,        difluoro-, or trifluoro-substituted);    -   —CO₂R^(d), wherein R^(d) is C₁₋₃ alkyl, preferably methyl or        ethyl; or    -   —N(R^(a))(R^(b)) wherein R^(a) and R^(b) are independently H, OH        (R^(a) and R^(b) are not both OH), C₁₋₃ alkyl (preferably CH₃),        C₁₋₆ hydroxyalkyl (preferably C₂₋₃ hydroxyalkyl, more preferably        —CH₂CH₂OH), or C₁₋₆ alkyl (preferably C₁₋₃ alkyl, more        preferably CH₃) that is optionally substituted with        —N(R^(e))(R^(f)) wherein R^(e) and R^(f) are independently H, OH        (R^(e) and R^(f) are not both OH), C₁₋₃ alkyl (preferably CH₃),        or C₂₋₃ hydroxyalkyl (preferably —CH₂CH2OH), and wherein        optionally R^(a) and R^(b) together may form a 3, 4, 5 or        6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and        morpholinyl);-   R₃ is H; halo; C₁₋₃ alkyl; or C₁₋₃ alkoxy;-   R₄ and R₆ are independently H; halo (preferably F or Cl); N₃, C₁₋₆    alkyl (preferably C₁₋₃, more preferably CH₃); C₁₋₃ alkoxy    (preferably OCH₃); or —N(R_(2b))(R_(2c)) wherein R_(2b) and R₂ are    independently H, OH, C₁₋₆ alkyl (preferably C₁₋₃ alkyl, more    preferably CH₃), C₁₋₆ hydroxyalkyl (preferably C₂₋₃ hydroxyalkyl,    more preferably CH₂CH2OH), or C₁₋₆ alkyl (preferably C₁₋₃ alkyl,    more preferably CH₃) that is optionally substituted with    —N(R_(2d))(R_(2e)) wherein R_(2d) and R₂, are independently H, OH,    C₁₋₃ alkyl (preferably CH₃) or C₂₋₃ hydroxyalkyl (preferably    —CH₂CH2OH), wherein R_(2b) and R_(2c) together may form a 3, 4, 5 or    6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and    morpholinyl), and wherein R_(2b) and R_(2c) are not both OH, R_(2d)    and R_(2e) are not both OH;-   R₅ is H or F, preferably H;-   R₇ and R₁₁ are independently H; halo (preferably F or Cl, more    preferably F); CH₃; or OCH₃;-   R₈ and R₁₀ are independently H; halo (preferably F or Cl, more    preferably Cl); OH; N₃; C₁₋₃ alkyl (preferably CH₃); C₁₋₃ alkoxy    (preferably OCH₃); C₁₋₃ haloalkyl (preferably monofluoromethyl,    difluoromethyl, trifluoromethyl); —XR_(9a), where X is O or S, and    R_(9a) is C₁₋₄ alkyl or C₁₋₃ haloalkyl (e.g., fluoroalkyl,    preferably fluoromethyl, i.e., CH₂F, CHF₂, CF₃); —NH(R^(a)) or    —N(R^(a))(R^(b)) where R^(a) and R^(b) are independently C₁₋₃ alkyl;    or —COOR_(9b), wherein R_(9b) is C₁₋₃ alkyl (preferably methyl or    ethyl). and-   R₉ is H; OH; N₃; halo;    -   C₁₋₃ alkyl (preferably methyl or ethyl) or C₁₋₃ haloalkyl        (preferably monofluoromethyl, difluoromethyl, trifluoromethyl);    -   —(C₀-₃ alkyl)C(O)N(R^(a))(R^(b)) where R^(a) and R^(b) are        independently H, C₂₋₄ hydroxyalkyl, C₁₋₃ alkyl, or or C₁₋₃ alkyl        optionally substituted with —N(R^(e))(R^(f)) where R^(e) and        R^(f) are independently H, OH (R^(a) and R^(b) are not both OH),        or C₁₋₃ alkyl; wherein optionally R^(a) and R^(b) together with        the N form a 3, 4, 5 or 6-membered heterocycle, and optionally        R^(e) and R^(f) together with the nitrogen atom to which they        both are linked form a 3, 4, 5 or 6-membered heterocycle;    -   —CO₂—R_(2f), wherein R_(2f) is an optionally substituted C₁₋₆        alkyl (preferably C₁₋₃ alkyl, more preferably methyl or ethyl),        the alkyl may be optionally substituted with OH, halo, C₁₋₃        alkoxy, amino, and C₁₋₃ alkylamino;    -   —XR_(2a) wherein X is S or O and R_(2a) is C₁₋₆ alkyl        (preferably C₁₋₃ alkyl, more preferably CH₃) optionally        substituted with a moiety selected from the group OH, halo, C₁₋₃        alkoxy, amino, and C₁₋₃ alkylamino; or    -   —N(R_(2b))(R_(2c)) wherein R_(2b) and R_(2c) are independently        H, OH, C₁₋₆ alkyl (preferably C₁₋₃ alkyl, more preferably CH₃),        C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl (preferably C₂₋₃ hydroxyalkyl,        more preferably —CH₂CH2OH), or C₁₋₆ alkyl (preferably C₁₋₃        alkyl, more preferably CH₃) that is optionally substituted with        —N(R_(2d))(R_(2e)) wherein R_(2d) and R_(2e) are independently        H, OH, C₁₋₃ alkyl (preferably CH₃) or C₂₋₃ hydroxyalkyl        (preferably —CH₂CH2OH), wherein optionally R_(2b) and R_(2c)        together with the nitrogen they both are linked to may form a 3,        4, 5 or 6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl,        and morpholinyl), and wherein R_(2b) and R_(2c) are not both OH,        R_(2d) and R_(2e) are not both OH; optionally, R₉ and one of R₈        and R₁₀ together form a 3, 4, 5 or 6-membered carbocycle or        heterocycle;-   exactly one of B and D is N provided that when B or D is N there is    no substituent at the N; and-   all of Q, T, U, and V are C;-   provided that when R₉ is H then R₈ and R₁₀ are not both H or one H    and the other halo.

Preferably when R₉ is H, R₈ or R₁₀ or both are independently OH; N₃;—XR_(9a), where X is O or S, and R_(9a) is C₁₋₄ alkyl or C₁₋₃ haloalkyl(e.g., fluoroalkyl, preferably fluoromethyl, i.e., CH₂F, CHF₂, CF₃);—NH(R^(a)) or —N(R^(a))(R^(b)) where R^(a) and R^(b) are independentlyC₁₋₃ alkyl; or —COOR_(9b), wherein R_(9b) is C₁₋₃ alkyl (preferablymethyl or ethyl). More preferably, when R₉ is H, R₈ or R₁₀ or both areindependently N₃, —OR_(9a), wherein R_(9a) is C₁₋₄ alkyl or C₁₋₃haloalkyl, or —N(R^(a))(R^(b)) where R^(a) and R^(b) are independentlyC₁₋₃ alkyl; or —COOR_(9b), wherein R_(9b) is C₁₋₃ alkyl (preferablymethyl or ethyl). Even more preferably when R₉ is H, R₈ or R₁₀ or bothare C₁₋₃ alkoxy or C₁₋₃ halo alkoxy.

Also preferably, when R₉ is C₁₋₆ alkyl, halo, or C₁₋₆ haloalkyl, then R₂is is not H and preferably R₂ is methyl, ethyl, Cl, F, fluoromethyl(CH₂F, CHF₂, CF₃), C₁₋₃ hydroxyalkyl (preferably CH₂OH or CH₂CH₂OH),NH₂, NH₂OH, —NHCH₂CH₂OH, NHCH₃, N(CH₃)₂, N₃, morpholino, OCH₃, OC₂H₅, orSCH₃.

In another preferred embodiment, compounds of the invention includecompounds of Formula VI or pharmaceutically acceptable salts or solvatesthereof, wherein:

-   R₁ is methyl or ethyl, and preferably methyl;-   R₂ is H; halo; N₃,    -   C₁₋₆ alkyl (preferably C₁₋₃ alkyl, more preferably CH₃)        optionally substituted with 1-4 substituents which are        independently OH or halo (preferably F, e.g., monofluoro,        difluoro, or trifluoro);    -   —XR_(2a) wherein X is S or O, and R_(2a) is C₁₋₆ alkyl        (preferably C₁₋₃ alkyl, more preferably CH₃) optionally        substituted with OH or halo (preferably F, e.g., monofluoro-,        difluoro-, or trifluoro-substituted);    -   —CO₂—R_(2f), wherein R_(2f) is C₁₋₆ (preferably C₁₋₃, more        preferably methyl or ethyl); or    -   —N(R_(2b))(R_(2c)) wherein R_(2b) and R_(2c) are independently        H, OH, C₁₋₆ alkyl (preferably C₁₋₃ alkyl, more preferably CH₃),        C₁₋₆ hydroxyalkyl (preferably C₂₋₃ hydroxyalkyl, more preferably        —CH₂CH2OH), or C₁₋₆ alkyl (preferably C₁₋₃ alkyl, more        preferably CH₃) that is optionally substituted with        —N(R_(2d))(R_(2e)) wherein R_(2d) and R_(2e) are independently        H, OH, C₁₋₃ alkyl (preferably CH₃), or C₂₋₃ hydroxyalkyl        (preferably CH₂CH₂OH), and wherein optionally R_(2b) and R_(2e)        together with the nitrogen they both are linked to may form a 3,        4, 5 or 6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl,        and morpholinyl), and wherein R_(2b) and R_(2c) are not both OH,        R_(2d) and R_(2e) are not both OH;-   R₃ is H; halo; C₁₋₃ alkyl; or C₁₋₃ alkoxy;-   R₄ and R₆ are independently H; halo (preferably F or CO; N_(3;) C₁₋₃    alkyl (preferably CH₃); C₁₋₃ alkoxy (preferably OCH₃); or    —N(R_(2b))(R_(2c)) wherein R_(2b) and R_(2c) are independently H,    OH, CH₃, and optionally R_(2b) and R₂ together with the nitrogen    they both are linked to may form a 3, 4, 5 or 6-membered heterocycle    (e.g., piperidinyl, pyrrolidinyl, and morpholinyl), and wherein    R_(2b) and R_(2c) are not both OH;-   R₅ is H;-   R₇ and R₁₁ are independently H, halo (preferably F), CH₃, or OCH₃;-   R₈ and R₁₀ are independently H; halo (preferably F or Cl, more    preferably F); C₁₋₃ alkyl (preferably CH₃); C₁₋₃ alkoxy (preferably    OCH₃); —XR_(9a), where X is O or S, and R_(9a) is C₁₋₄ alkyl or C₁₋₃    haloalkyl (e.g., fluoroalkyl, preferably fluoromethyl, i.e., CH₂F,    CHF₂, CF₃); —N(R^(a))(R^(b)) where R^(a) and R^(b) are independently    C₁₋₃ alkyl; or —COOR_(9b), wherein R_(9b) is C₁₋₃ alkyl (preferably    methyl or ethyl); and-   R₉ is selected from the group:    -   hydrogen; hydroxy; N₃;    -   C₁₋₃ alkyl (preferably methyl or ethyl) or C₁₋₃ haloalkyl        (preferably monofluoromethyl, difluoromethyl, trifluoromethyl);    -   —OR_(9a), wherein R_(9a) is C₁₋₃ alkyl (i.e., methyl, ethyl,        propyl, isopropyl) or C₁₋₃ haloalkyl (e.g., fluoroalkyl,        preferably fluoromethyl, i.e., CH₂F, CHF₂, CF₃);    -   —N(R_(2b))(R_(2c)) wherein R_(2b) and R_(2c) are independently        H, C₁₋₃ alkyl, or C₁₋₃ haloalkyl;or    -   —COOR_(9b), wherein R_(9b) is C₁₋₃ alkyl (preferably methyl or        ethyl); and optionally R₉ and one of R₈ and R₁₀ together form a        3, 4, 5, or 6-membered hetercycle;-   exactly one of B and D is N provided that when B or D is N there is    no substituent at the N; and-   all of Q, T, U, and V are C;-   provided that when R₉ is H at least one of R₈ and R₁₀ is not H or    halo, preferably at least one of R₈ and R₁₀ is not H or halo or C₁₋₃    alkyl.

Preferably in this embodiment, when R₉ is H, R₈ or R₁₀ or both areindependently —XR_(9a), where X is O or S, and R_(9a) is C₁₋₄ alkyl orC₁₋₃ haloalkyl (e.g., fluoroalkyl, preferably fluoromethyl, i.e., CH₂F,CHF₂, CF₃); —N(R^(a))(R^(b)) where R^(a) and R^(b) are independentlyC₁₋₃ alkyl; or —COOR_(9b), wherein R_(9b) is C₁₋₃ alkyl (preferablymethyl or ethyl). More preferably, when R₉ is H, R₈ or R₁₀ or both areindependently N₃, —OR_(9a), wherein R_(9a) is C₁₋₄ alkyl or C₁₋₃haloalkyl, or —N(R^(a))(R^(b)) where R^(a) and R^(b) are independentlyC₁₋₃ alkyl; or —COOR_(9b), wherein R_(9b) is C₁₋₃ alkyl (preferablymethyl or ethyl). Even more preferably when R₉ is H, R₈ or R₁₀ or bothare C₁₋₃ alkoxy or C₁₋₃ halo alkoxy.

Also preferably in this embodiment, when R₉ is H then R₈ and R₁₀ are notboth H or one H and the other halo, and R₂ is not H.

Also preferably, in this embodiment, when R₉ is C₁₋₆ alkyl, halo, orC₁₋₆ haloalkyl, then R₂ is not H and preferably R₂ is methyl, ethyl, Cl,F, fluoromethyl (CH₂F, CHF₂, CF₃), C₁₋₃ hydroxyalkyl (preferably CH₂OHor CH₂CH₂OH), NH₂, NH₂OH, —NHCH₂CH₂OH, NHCH₃, N(CH₃)₂, N₃, morpholino,OCH₃, OC₂H₅, or SCH₃.

Also preferably, in this embodiment, when R₉ is H, R₈ or R₁₀ or both areOCH₃ and preferably R₇ and R₁₁ are H, and also preferably R₂ is nothydrogen and preferably R₂ is methyl or chloro. Also preferably in thisembodiment, when R₉ is alkyl or haloalkyl or chloro, R₂ is not hydrogenand preferably R₂ is methyl or chloro.

In another preferred embodiment, compounds of the invention includecompounds of Formula VI or pharmaceutically acceptable salts or solvatesthereof, wherein:

-   R₁ is methyl or ethyl, and preferably methyl;-   R₂ is H; halo; N₃;    -   C₁₋₆ alkyl (preferably C₁₋₃ alkyl, more preferably CH₃)        optionally substituted with 1-4 substituents which are OH or        halo (preferably F, e.g., monofluoro, difluoro, or trifluoro);    -   —XR_(2a) wherein X is S or O, and R_(2a) is C₁₋₆ alkyl        (preferably C₁₋₃ alkyl, more preferably CH₃) optionally        substituted with OH or halo (preferably F, e.g., monofluoro-,        difluoro-, or trifluoro-substituted); or    -   —N(R_(2b))(R_(2c)) wherein R_(2b) and R_(2c) are independently        H, OH, C₁₋₆ alkyl (preferably C₁₋₃ alkyl), C₁₋₆ hydroxyalkyl        (preferably C₂₋₃ hydroxyalkyl, more preferably —CH₂CH2OH), or        R_(2b) and R_(2c) together form a 3, 4, 5 or 6-membered        heterocycle (e.g., piperidinyl, pyrrolidinyl, and morpholinyl);-   R₃ is H; halo; C₁₋₃ alkyl; or C₁₋₃ alkoxy;-   R₄ and R₆ are independently H; halo (preferably F or Cl); N_(3;)    C₁₋₃ alkyl (preferably CH₃); C₁₋₃ alkoxy (preferably OCH₃); or    —N(R_(2b))(R_(2c)) wherein R_(2b) and R₂ are independently H, OH    (R_(2b) and R_(2c) are not both OH), CH₃, or R_(2b) and R₂ together    form a 3, 4, 5 or 6-membered heterocycle (e.g., piperidinyl,    pyrrolidinyl, and morpholinyl);-   R₅ is H or F, preferably H;-   R₇ and R₁₁ are independently H, halo (preferably F), C₁₋₃ alkyl    (preferably CH₃), C₁₋₃ alkoxy (preferably OCH₃), or C₁₋₃ alkylthiol;    Preferably R₇ and R₁₁ are independently H, halo or methoxy;-   R₈ and R₁₀ are independently H; halo (preferably F or Cl); C₁₋₃    alkyl (preferably CH₃); C₁₋₃ alkoxy (preferably OCH₃) or C₁₋₃    alkylthiol; and-   R₉ is selected from the group:    -   hydrogen; hydroxy; Cl; N₃;    -   C₁₋₃ alkyl (preferably methyl or ethyl) or C₁₋₃ haloalkyl        (preferably monofluoromethyl, difluoromethyl, trifluoromethyl);    -   —OR_(9a), wherein R₁₂ is C₁₋₃ alkyl (i.e., methyl, ethyl,        propyl, isopropyl) or C₁₋₃ haloalkyl (e.g., fluoroalkyl,        preferably fluoromethyl, i.e., CH₂F, CHF₂, CF₃);    -   —N(R_(2b))(R_(2c)) wherein R_(2b) and R₂ are independently C₁₋₃        alkyl;or    -   —COOR_(9b), wherein R_(9b) is C₁₋₃ alkyl (preferably methyl or        ethyl); and optionally R₉ and one of R₈ and R₁₀ together form a        3, 4, 5, or 6-membered heterocycle;-   exactly one of B and D is N provided that when B or D is N there is    no substituent at the N; and-   all of Q, T, U, and V are C;-   provided that when R₉ is H at least one of R₈ and R₁₀ is not H or    halo, preferably at least one of R₈ and R₁₀ is not H or halo or C₁₋₃    alkyl.

Preferably in this embodiment, when R₉ is H, R₈ or R₁₀ or both areindependently C₁₋₃ alkoxy (preferably OCH₃) or C₁₋₃ alkylthiol, eachbeing optionally substituted with 1-4 F. Even more preferably when R₉ isH, R₈ or R₁₀ or both are methoxy or ethoxy. Also preferably R₂ is not H.

Also preferably, when R₉ is C₁₋₃ alkyl, halo, or C₁₋₃ haloalkyl, then R₂is not H, preferably R₂ is methyl, ethyl, Cl, F, fluoromethyl (CH₂F,CHF₂, CF₃), C₁₋₃ hydroxyalkyl (preferably CH₂OH or CH₂CH₂OH), NH₂,NH₂OH, —NHCH₂CH₂OH, NHCH₃, N(CH₃)₂, N₃, morpholino, OCH₃, OC₂H₅, orSCH₃.

Also preferably, in this embodiment, when R₉ is H, R₈ or R₁₀ or both areOCH₃ and preferably R₇ and R₁₁ are H, and also preferably R₂ is nothydrogen and preferably R₂ is methyl or chloro. Also preferably in thisembodiment, when R₉ is alkyl or haloalkyl or chloro, R₂ is not hydrogenand preferably R₂ is methyl or chloro.

In another preferred embodiment, compounds of the invention includecompounds of Formula VI or pharmaceutically acceptable salts or solvatesthereof, wherein:

-   R₁ is methyl or ethyl, preferably methyl;-   R₂ is H, methyl, ethyl, Cl, F, fluoromethyl (CH₂F, CHF₂, CF₃), C₁₋₃    hydroxyalkyl (preferably CH₂OH or CH₂CH₂OH), NH₂, NH₂OH,    —NHCH₂CH₂OH, NHCH₃, N(CH₃)₂, N₃, morpholino, OCH₃, OC₂H₅, or SCH₃;    R₃ is H, CH₃, OCH₃, F, or Cl, R₄ and R₆ are independently H, CH₃,    NH₂, N₃, F, or Cl; R₅ is H; R₇ and R₁₁ are independently H, F, or    OCH₃; R₈ and R₁₀ are independently H, F, Cl, or OCH₃; and-   R₉ is selected from the group:    -   H; OH; N₃,    -   C₁₋₃ alkyl (preferably methyl or ethyl) or C₁₋₃ haloalkyl        (preferably monofluoromethyl, difluoromethyl, trifluoromethyl);    -   —OR_(9a), wherein R_(9a) is C₁₋₃ alkyl (i.e., methyl, ethyl,        propyl, isopropyl) or C₁₋₃ haloalkyl (e.g., fluoroalkyl,        preferably fluoromethyl, i.e., CH₂F, CHF₂, CF₃);    -   —N(R_(2b))(R_(2c)) wherein R_(2b) and R₂ are independently C₁₋₃        alkyl; or    -   —COOR_(9b), wherein R_(9b) is C₁₋₃ alkyl (preferably methyl or        ethyl), and optionally R₈ and R₉ together form a 3, 4, 5, or        6-membered heterocycle;-   exactly one of B and D is N provided that when B or D is N there is    no substituent at the N; and-   all of Q, T, U, and V are C;-   provided that when R₉ is H, at least one of R₈ and R₁₀ is OCH₃, and    when R₉ is C₁₋₃ alkyl or C₁₋₃ haloalkyl or Cl then R₂ is Cl or    methyl or ethyl.

Preferably in this embodiment, when R₉ is H, R₈ or R₁₀ or both areindependently C₁₋₃ alkoxy (preferably OCH₃) or C₁₋₃ alkylthiol, eachbeing optionally substituted with 1-4 F. Even more preferably when R₉ isH, R₈ or R₁₀ or both are methoxy or ethoxy. Also preferably R₂ is not H.

Also preferably, when R₉ is C₁₋₃ alkyl, halo, or C₁₋₃ haloalkyl, then R₂is not H, preferably R₂ is methyl, ethyl, Cl, F, fluoromethyl (CH₂F,CHF₂, CF₃), C₁₋₃ hydroxyalkyl (preferably CH₂OH or CH₂CH₂OH), NH₂,NH₂OH, —NHCH₂CH₂OH, NHCH₃, N(CH₃)₂, N₃, morpholino, OCH₃, OC₂H₅, orSCH₃.

Also preferably, in this embodiment, when R₉ is H, R₈ or R₁₀ or both areOCH₃ and preferably R₇ and R₁₁ are H, and also preferably R₂ is nothydrogen and preferably R₂ is methyl or chloro. Also preferably in thisembodiment, when R₉ is alkyl or haloalkyl or chloro, R₂ is not hydrogenand preferably R₂ is methyl or chloro.

In another preferred embodiment, compounds of the invention includecompounds of Formula VI or pharmaceutically acceptable salts or solvatesthereof, wherein:

-   R₁ is CH₃;-   R₂ is H, methyl, ethyl, Cl, F, fluoromethyl (CH₂F, CHF₂, CF₃),    CH₂OH, NH₂, NHCH₃, N(CH₃)₂, —NHCH₂CH₂OH, OCH₃, or SCH₃; R₃ is H,    CH₃, OCH₃, F, or Cl; R₄ and R₆ are independently H, CH₃, NH₂, F, or    Cl; R₅ is H; R₇ and R₁₁ are independently H, F, or OCH₃; R₈ and R₁₀    are independently H, F, Cl, or OCH₃; and-   R₉ is selected from the group:-   —OR₁₂, wherein R₁₂ is selected from the group of methyl, ethyl,    fluoromethyl (e.g., CH₂F, CHF₂, CF₃), and fluoroethyl;    -   —NHCH₃;    -   —N(CH₃)₂;    -   —N₃; and    -   —COOR₁₃, wherein R₁₃ is methyl or ethyl;-   exactly one of B and D is N provided that when B or D is N there is    no substituent at the N; and-   all of Q, T, U, and V are C.

In a more preferred embodiment, compounds of the invention includecompounds of Formula VI or pharmaceutically acceptable salts or solvatesthereof, wherein:

-   R₁ is CH₃;-   R₂ is H, methyl, Cl, —CH₂OH, —NH₂, —NHCH₃, —NHCH₂CH₂OH, —OCH₃,    —SCH₃, or —CH₂F;-   R₃ is H, —CH₃, —OCH₃, or Cl;-   R₄ is H, CH₃, or NH₂;-   R₅ is H;-   R₆ is H, or CH₃;-   R₇ and R₁₁ are independently H, or F;-   R₈ and R₁₀ are independently H, or F or OCH₃; and-   R₉ is —OCH₃ or —OC₂H₅, —N(CH₃)₂, —CO₂CH₃, —OCHF₂, or N₃;-   exactly one of B and D is N provided that when B or D is N there is    no substituent at the N; and-   all of Q, T, U, and V are C.

In a more preferred embodiment, the present invention provides compoundsof Formula VI or pharmaceutically acceptable salts or solvates thereof,wherein R₁ is CH₃; R₂ is Cl, methyl, or CH₂F; R₃ is H, CH₃, F, or Cl;R₄, R₅ and R₆ are H; R₇, R₈, R₁₀ and R₁₁ are independently H or F; andR₉ is —OCH₃ or —N(CH₃)₂, exactly one of B and D is N provided that whenB or D is N there is no substituent at the N; and all of Q, T, U, and Vare C.

Specifically, one group of the compounds of Formula VI are thoserepresented by Formula VIa:

-   or pharmaceutically acceptable salts or solvates thereof, wherein:-   R₁ is methyl or ethyl, preferably methyl;-   R₅ is H or F, preferably H;-   R₂-R₄, R₆-R₁₁ are independently H, halo, N₃, OH, thiol, nitro, CN,    NH₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆    alkylthiol, halo-C₁₋₆ alkyl, C₂₋₆ alkenyl-O—, C₂₋₆ alkynyl-O,    hydroxy-C₁₋₆ alkyl, C₁₋₆ alkoxy-C₁₋₆ alkyl, C₁₋₆ acyl, C₁₋₆ acyloxy,    —C₁₋₆ alkyl-C(O)O—C₁₋₆ alkyl, —C(O)O—C₁₋₆ alkyl, C₁₋₆    alkyl-C(O)O—C₁₋₆ alkyl-, C₁₋₆ acylamido, —N(R^(a))(R^(b)), —C₁₋₆    alkyl-C(O)N(R^(a))(R^(b)), —C (O)N(R^(a))(R^(b)),    N(R^(a))(R^(b))—C₁₋₆ alkyl, 3, 4, 5, or 6-membered carbocycle,    heterocycle, aryl, or heteroaryl, wherein R^(a) and R^(b) are    independently H, OH (R^(a) and R^(b) are not both OH), C₂₋₆    hydroxyalkyl, or C₁₋₆ alkyl, or R^(a) and R^(b) together with the    nitrogen atom to which they are both linked to form a 3, 4, 5 or    6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and    morpholinyl); wherein any of the groups is optionally substituted    with 1-3 substituents wherein each substituent is independently    halo, N₃, OH, thiol, nitro, CN, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆    alkynyl, C₁₋₆ alkoxy, C₁₋₆ alkylthiol, C₂₋₆ alkenyl-O—, C₂₋₆    alkynyl-O—, hydroxy-C₁₋₆ alkyl, C₁₋₆ alkoxy-C₁₋₆ alkyl, C₁₋₆ acyl,    C₁₋₆ acyloxy, —C₁₋₆ alkyl-C(O)O—C₁₋₆ alkyl, —C(O)O—C₁₋₆ alkyl, C₁₋₆    alkyl-C(O)O—C₁₋₆ alkyl-, C₁₋₆ acylamido, —N(R^(a))(R^(b)), —C₁₋₆    alkyl-C(O)N(R^(a))(R^(b)), —C(O)N(R^(a))(R^(b)),    N(R^(a))(R^(b))—C₁₋₆ alkyl-, wherein R^(a) and R^(b) are    independently H, OH (R^(a) and R^(b) are not both OH), C₂₋₆    hydroxyalkyl, or C₁₋₆ alkyl or R^(a) and R^(b) together with the    nitrogen atom to which they are both linked form a 3, 4, 5 or    6-membered heterocycle, wherein optionally any two adjacent R₇-R₁₁    groups together form a 3, 4, 5 or 6-membered carbocycle or    heterocycle; and-   Q, T, U and V are independently C or N, wherein at least one of Q,    T, U and V is N, and when Q, T, U or V is N there is no substituent    at the N, provided that when R₉ is H then R₈ and R₁₀ are not both H,    or one H and the other alkyl. Preferably when R₉ is H then at least    one of R₈ and R₁₀ is not H or alkyl. More preferably, when R₉ is H    then at least one of R₈ and R₁₀ is not H, alkyl, or halo.

In one embodiment, R₉ is selected from the group consisting of H, OH,Cl, N_(3;)

C₁₋₆ alkyl (preferably C₁₋₃ alkyl, more preferably CH₃) optionallysubstituted with 1, 2 or 3 substituents, each substituent beingindependently OH, halo, C₁₋₃ alkoxy, (halo)C₁₋₃ alkoxy, —N(R^(a))(R^(b))where R^(a) and R^(b) are independently H, OH (R^(a) and R^(b) are notboth OH), C₂₋₄ hydroxyalkyl, or C₁₋₃ alkyl or R^(a) and R^(b) togetherwith the nitrogen atom to which they are both linked to form a 3, 4, 5or 6-membered heterocycle;

—XR^(c) wherein X is S or O and R^(c) is C₁₋₆ alkyl (preferably C₁₋₃alkyl, more preferably CH₃) optionally substituted with with 1, 2 or 3substituents, each substituent being independently OH, halo, C₁₋₃alkoxy, or (halo)C₁₋₃ alkoxy;

—(C₀₋₃ alkyl)CO₂R^(d), wherein R^(d) is an C₁₋₆ alkyl (preferably C₁₋₃alkyl, more preferably methyl or ethyl) optionally substituted with 1, 2or 3 substituents, each substituent being independently OH, halo, C₁₋₃alkoxy (e.g., fluoroalkoxy), —N(R^(a))(R^(b)) where R^(a) and R^(b) areindependently H, OH (R^(a) and R^(b) are not both OH), C₂₋₄hydroxyalkyl, or C₁₋₃ alkyl or R^(a) and R^(b) together with thenitrogen atom to which they both are linked form a 3, 4, 5 or 6-memberedheterocycle;

—N(R^(a))(R^(b)) where R^(a) and R^(b) are independently H, OH (R^(a)and R^(b) are not both OH), C₂₋₄ hydroxyalkyl, C₁₋₃ alkyl, or C₁₋₃ alkylsubstituted with —N(R^(e))(R^(f)) where R^(e) and R^(f) areindependently H, OH (R^(e) and R^(f) are not both OH), or C₁₋₃ alkyl;wherein optionally R^(a) and R^(b) together with the N form a 3, 4, 5 or6-membered heterocycle, and optionally R^(e) and R^(f) together with thenitrogen atom to which they both are linked form a 3, 4, 5 or 6-memberedheterocycle; or

—(C₀₋₃ alkyl)C(O)N(R^(a))(R^(b)) where R^(a) and R^(b) are independentlyH or C₁₋₃ alkyl; and optionally R₉ and one of R₈ and R₁₀ together form a3, 4, 5, or 6-membered heterocycle; preferably R₉ is selected from thegroup outlined above except R₉ is not H and C₁₋₆alkyl.

In another embodiment, R₉ is H; OH; Cl; N₃; C₁₋₃ alkyl (preferablymethyl; C₁₋₃ haloalkyl (preferably monofluoromethyl, difluoromethyl,trifluoromethyl); —OR_(9a), wherein R_(9a) is C₁₋₄ alkyl or C₁₋₃haloalkyl (e.g., fluoroalkyl, preferably fluoromethyl, i.e., CH₂F, CHF₂,CF₃); —NH(R^(a)); —N(R^(a))(R^(b)) where R^(a) and R^(b) areindependently C₁₋₃ alkyl; or —COOR_(9b), wherein R_(9b) is C₁₋₃ alkyl(preferably methyl or ethyl); and optionally R₉ and one of R₈ and R₁₀together form a 3, 4, 5, or 6-membered heterocycle; preferably R₉ isselected from the group outlined above except R₉ is not H or C ₁₋₃alkyl

In a preferred embodiment, R₉ is N₃, —OR_(9a) wherein R_(9a) is C₁₋₃alkyl optionally substituted with 1-7 F, —N(R^(a))(R^(b)) where R^(a)and R^(b) are independently C₁₋₃ alkyl, —COOR_(9b) where R_(9b) is C₁₋₃alkyl.

In a more preferred embodiment, R₉ is —OCH₃, —OC₂H₅, —N(CH₃)₂, —CO₂CH₃,—OCHF₂, or N₃.

In the various embodiments of the compounds according to Formula VIapreferably when R₉ is H, R₈ or R₁₀ or both are independently OH; Cl; N₃;—XR_(9a), where X is O or S, and R_(9a) is C₁₋₄ alkyl or C₁₋₃ haloalkyl(e.g., fluoroalkyl, preferably fluoromethyl, i.e., CH₂F, CHF₂, CF₃);—NH(R^(a)) or —N(R^(a))(R^(b)) where R^(a) and R^(b) are independentlyC₁₋₃ alkyl; or —COOR_(9b), wherein R_(9b) is C₁₋₃ alkyl (preferablymethyl or ethyl). More preferably, when R₉ is H, R₈ or R₁₀ or both areindependently N₃, —OR_(9a), wherein R_(9a) is C₁₋₄ alkyl or C₁₋₃haloalkyl; —N(R^(a))(R^(b)) where R^(a) and R^(b) are independently C₁₋₃alkyl; or —COOR_(9b), wherein R_(9b) is C₁₋₃ alkyl (preferably methyl orethyl). Even more preferably when R₉ is H, R₈ or R₁₀ or both are C₁₋₃alkoxy or C₁₋₃ haloalkoxy.

Also preferably in the various embodiments, when R₉ is H then R₂ is notH, and preferably R₂ is halo; C₁₋₃ alkyl optionally substituted with OHor halo (preferably F, e.g., monofluoro, difluoro, or trifluoro);—XR_(2a) wherein X is S or O and R_(2a) is C₁₋₃ alkyl (preferably C₁₋₃alkyl, more preferably CH₃) optionally substituted with halo (preferablyF, e.g., monofluoro-, difluoro-, or trifluoro-substituted); or—N(R^(a))(R^(b)) wherein R^(a) and R^(b) are independently H, OH (R^(a)and R^(b) are not both OH), C₁₋₃ alkyl (preferably CH₃), C₂₋₃hydroxyalkyl. More preferably R₂ is methyl, ethyl, Cl, F, fluoromethyl(CH₂F, CHF₂, CF₃), C₁₋₃ hydroxyalkyl (preferably CH₂OH or CH₂CH₂OH),NH₂, NH₂OH, —NHCH₂CH₂OH, NHCH₃, N(CH₃)₂, N₃, morpholino, OCH₃, OC₂H₅, orSCH₃.

Also preferably, when R₉ is C₁₋₆ alkyl or C₁₋₆ haloalkyl, R₂ is not H,and preferably is methyl, ethyl, Cl, F, fluoromethyl (CH₂F, CHF₂, CFAC₁₋₃ hydroxyalkyl (preferably CH₂OH or CH₂CH₂OH), NH₂, NH₂OH,—NHCH₂CH₂OH, NHCH₃, N(CH₃)₂, N₃, morpholino, OCH₃, OC₂H₅, or SCH₃.

In one embodiment, R₂ is H; halo; N₃; C₁₋₆ alkyl (preferably C₁₋₃ alkyl,more preferably CH₃) optionally substituted with OH or halo (preferablyF, e.g., monofluoro, difluoro, or trifluoro); —XR_(2a) wherein X is S orO, and R_(2a) is C₁₋₆ alkyl (preferably C₁₋₃ alkyl, more preferably CH₃)optionally substituted with OH or halo (preferably F, e.g., monofluoro-,difluoro-, or trifluoro-substituted); —CO₂R^(d), wherein R^(d) is C₁₋₃alkyl, preferably methyl or ethyl; or —N(R^(a))(R^(b)) wherein R^(a) andR^(b) are independently H, OH (R^(a) and R^(b) are not both OH), C₁₋₃alkyl (preferably CH₃), C₁₋₆ hydroxyalkyl (preferably C₂₋₃ hydroxyalkyl,more preferably —CH₂CH₂OH), or C₁₋₆ alkyl (preferably C₁₋₃ alkyl, morepreferably CH₃) that is optionally substituted with —N(R^(e))(R^(f))wherein R^(e) and R^(f) are independently H, OH (R^(e) and R^(f) are notboth OH), C₁₋₃ alkyl (preferably CH₃), or C₂₋₃ hydroxyalkyl (preferably—CH₂CH2OH), and wherein optionally R^(a) and R^(b) together with the Nthey are both linked to may form a 3, 4, 5 or 6-membered heterocycle.

In a preferred embodiment, R₂ is H; halo; C₁₋₃ alkyl optionallysubstituted with OH or halo (preferably F, e.g., monofluoro, difluoro,or trifluoro); —XR_(2a) wherein X is S or O and R_(2a) is C₁₋₃ alkyl(preferably C₁₋₃ alkyl, more preferably CH₃) optionally substituted withhalo (preferably F, e.g., monofluoro-, difluoro-, ortrifluoro-substituted); or —N(R^(a))(R^(b)) wherein R^(a) and R^(b) areindependently H, OH (R^(a) and R^(b) are not both OH), C₁₋₃ alkyl(preferably CH₃), C₂₋₃ hydroxyalkyl.

In preferred embodiments, R₂ is H, methyl, ethyl, Cl, F, fluoromethyl(CH₂F, CHF₂, CF₃), C₁₋₃ hydroxyalkyl (preferably CH₂OH or CH₂CH₂OH),NH₂, NH₂OH, —NHCH₂CH₂OH, NHCH₃, N(CH₃)₂, N₃, morpholino, OCH₃, OC₂H₅, orSCH₃.

In more preferred embodiments, R₂ is H, methyl, Cl, —CH₂OH, —NH₂,—NHCH₃, —NHCH₂CH₂OH, —OCH₃, —SCH₃, or —CH₂F.

In all embodiments of the compound of Formula VIa, it is preferred thatone or two of Q, T, U and V are N. For example Q and V are N and T and Uare C.

In one embodiment, compounds of the invention include compounds ofFormula VIa or pharmaceutically acceptable salts or solvates thereof,wherein:

-   R₁ is methyl or ethyl, preferably methyl;-   R₂ is H; halo; N_(3;)    -   C₁₋₆ alkyl (preferably C₁₋₃ alkyl, more preferably CH₃)        optionally substituted with OH or halo (preferably F, e.g.,        monofluoro, difluoro, or trifluoro);    -   —XR_(2a) wherein X is S or O, and R_(2a) is C₁₋₆ alkyl        (preferably C₁₋₃ alkyl, more preferably CH₃) optionally        substituted with OH or halo (preferably F, e.g., monofluoro-,        difluoro-, or trifluoro-substituted);    -   —CO₂R^(d), wherein R^(d) is C₁₋₃ alkyl, preferably methyl or        ethyl; or    -   —N(R^(a))(R^(b)) wherein R^(a) and R^(b) are independently H, OH        (R^(a) and R^(b) are not both OH), C₁₋₃ alkyl (preferably CH₃),        C₁₋₆ hydroxyalkyl (preferably C₂₋₃ hydroxyalkyl, more preferably        —CH₂CH₂OH), or C₁₋₆ alkyl (preferably C₁₋₃ alkyl, more        preferably CH₃) that is optionally substituted with        —N(R^(e))(R^(f)) wherein R^(e) and R^(f) are independently H, OH        (R^(e) and R^(f) are not both OH), C₁₋₃ alkyl (preferably CH₃),        or C₂₋₃ hydroxyalkyl (preferably —CH₂CH2OH), and wherein        optionally R^(a) and R^(b) together with the N they are both        linked to may form a 3, 4, 5 or 6-membered heterocycle (e.g.,        piperidinyl, pyrrolidinyl, and morpholinyl);-   R₃ is H; halo; C₁₋₃ alkyl; or C₁₋₃ alkoxy;-   R₄ and R₆ are independently H; halo (preferably F or CO; N₃; C₁₋₆    alkyl (preferably C₁₋₃, more preferably CH₃); C₁₋₃ alkoxy    (preferably OCH₃); or —N(R_(2b))(R_(2c)) wherein R_(2b) and R_(c)    are independently H, OH, C₁₋₆ alkyl (preferably C₁₋₃ alkyl, more    preferably CH₃), C₁₋₆ hydroxyalkyl (preferably C₂₋₃ hydroxyalkyl,    more preferably —CH₂CH2OH), or C₁₋₆ alkyl (preferably C₁₋₃ alkyl,    more preferably CH₃) that is optionally substituted with    —N(R_(2d))(R_(2e)) wherein R_(2d) and R_(2e) are independently H,    OH, C₁₋₃ alkyl (preferably CH₃) or C₂₋₃ hydroxyalkyl (preferably    —CH₂CH2OH), wherein R_(2b) and R_(2c) together with the N they are    both linked to may form a 3, 4, 5 or 6-membered heterocycle (e.g.,    piperidinyl, pyrrolidinyl, and morpholinyl), and wherein R_(2b) and    R_(2c) are not both OH, R_(2d) and R₂, are not both OH;-   R₅ is H or F, preferably H;-   R₇ and R₁₁ are independently H; halo (preferably F or Cl, more    preferably F); CH₃; or OCH₃;-   R₈ and R₁₀ are independently H; halo (preferably F or Cl, more    preferably Cl); OH; N₃; C₁₋₃ alkyl (preferably CH₃); C₁₋₃ alkoxy    (preferably OCH₃); C₁₋₃ haloalkyl (preferably monofluoromethyl,    difluoromethyl, trifluoromethyl); —XR_(9a), where X is O or S, and    R_(9a) is C₁₋₄ alkyl or C₁₋₃ haloalkyl (e.g., fluoroalkyl,    preferably fluoromethyl, i.e., CH₂F, CHF₂, CF₃); —NH(R^(a)) or    —N(R^(a))(R^(b)) where R^(a) and R^(b) are independently C₁₋₃ alkyl;    or —COOR_(9b), wherein R_(9b) is C₁₋₃ alkyl (preferably methyl or    ethyl);-   R₉ is selected from the group consisting of H, OH, Cl, N₃,

C₁₋₆ alkyl (preferably C₁₋₃ alkyl, more preferably CH₃) optionallysubstituted with 1, 2 or 3 substituents, each substituent beingindependently OH, halo, C₁₋₃ alkoxy, (halo)C₁₋₃ alkoxy, —N(R^(a))(R^(b))where R^(a) and R^(b) are independently H, OH (R^(a) and R^(b) are notboth OH), C₂₋₄ hydroxyalkyl, or C₁₋₃ alkyl or R^(a) and R^(b) togetherwith the nitrogen atom to which they are both linked form a 3, 4, 5 or6-membered heterocycle;

—XR^(c) wherein X is S or O and R^(c) is C₁₋₆ alkyl (preferably C₁₋₃alkyl, more preferably CH₃) optionally substituted with with 1, 2 or 3substituents, each substituent being independently OH, halo, C₁₋₃alkoxy, or (halo)C₁₋₃ alkoxy;

—(C₀₋₃ alkyl)CO₂R^(d), wherein R^(d) is an C₁₋₆ alkyl (preferably C₁₋₃alkyl, more preferably methyl or ethyl) optionally substituted with 1, 2or 3 substituents, each substituent being independently OH, halo, C₁₋₃alkoxy (e.g., fluoroalkoxy), —N(R^(a))(R^(b)) where R^(a) and R^(b) areindependently H, OH (R^(a) and R^(b) are not both OH), C₂₋₄hydroxyalkyl, or C₁₋₃ alkyl or R^(a) and R^(b) together with thenitrogen atom to which they both are linked form a 3, 4, 5 or 6-memberedheterocycle;

—N(R^(a))(R^(b)) where R^(a) and R^(b) are independently H, OH (R^(a)and R^(b) are not both OH), C₂₋₄ hydroxyalkyl, C₁₋₃ alkyl, or C₁₋₃ alkylsubstituted with —N(R^(e))(R^(f)) where R^(e) and R^(f) areindependently H, OH (R^(e) and R^(f) are not both OH), or C₁₋₃ alkyl;wherein optionally R^(a) and R^(b) together with the N form a 3, 4, 5 or6-membered heterocycle, and optionally R^(e) and R^(f) together with thenitrogen atom to which they both are linked form a 3, 4, 5 or 6-memberedheterocycle; or

—(C₀₋₃ alkyl)C(O)N(R^(a))(R^(b)) where R^(a) and R^(b) are independentlyH or C₁₋₃ alkyl; and optionally R₉ and one of R₈ and R₁₀ together form a3, 4, 5, or 6-membered heterocycle; provided that when R₉ is H, at leastone of R₈ and R₁₀ is not hydrogen or alkyl; and

-   Q, T, U and V are independently C or N, provided that at least one    of Q, T, U and V is N, wherein when Q, T, U or V is N, then there is    no substituent at the N. In some specific embodiments, one or two of    Q, T, U and V are N.

Preferably when R₉ is H, R₈ or R₁₀ or both are independently OH; Cl; N₃;—XR_(9a), where X is O or S, and R_(9a) is C₁₋₄ alkyl or C₁₋₃ haloalkyl(e.g., fluoroalkyl, preferably fluoromethyl, i.e., CH₂F, CHF₂, CF₃);NH(R^(a)) or N(R^(a))(R^(b)) where R^(a) and R^(b) are independentlyC₁₋₃ alkyl; or —COOR_(9b), wherein R_(9b) is C₁₋₃ alkyl (preferablymethyl or ethyl). More preferably, when R₉ is H, R₈ or R₁₀ or both areindependently N₃, —OR_(9a), wherein R_(9a) is C₁₋₄ alkyl or C₁₋₃haloalkyl, or —N(R^(a))(R^(b)) where R^(a) and R^(b) are independentlyC₁₋₃ alkyl; or —COOR_(9b), wherein R_(9b) is C₁₋₃ alkyl (preferablymethyl or ethyl). Even more preferably when R₉ is H, R₈ or R₁₀ or bothare C₁₋₃ alkoxy or C₁₋₃ haloalkoxy.

Also preferably, when R₉ is C₁₋₆ alkyl or C₁₋₆ haloalkyl, R₂ is methyl,ethyl, Cl, F, fluoromethyl (CH₂F, CHF₂, CF₃), C₁₋₃ hydroxyalkyl(preferably CH₂OH or CH₂CH₂OH), NH₂, NH₂OH, —NHCH₂CH₂OH, NHCH₃, N(CH₃)₂,N₃, morpholino, OCH₃, OC₂H₅, or SCH₃.

In another preferred embodiment, compounds of the invention includecompounds of Formula VIa or pharmaceutically acceptable salts orsolvates thereof, wherein:

-   R₁ is methyl or ethyl, and preferably methyl;-   R₂ is H; halo; N₃;    -   C₁₋₆ alkyl (preferably C₁₋₃ alkyl, more preferably CH₃)        optionally substituted with OH or halo (preferably F, e.g.,        monofluoro, difluoro, or trifluoro);    -   —XR_(2a) wherein X is S or O, and R_(2a) is C₁₋₆ alkyl        (preferably C₁₋₃ alkyl, more preferably CH₃) optionally        substituted with OH or halo (preferably F, e.g., monofluoro-,        difluoro-, or trifluoro-substituted);    -   —CO₂—R_(2f), wherein R_(2f) is C₁₋₆ alkyl (preferably C₁₋₃        alkyl, more preferably methyl or ethyl); or    -   —N(R_(2b))(R_(2c)) wherein R_(2b) and R_(2e) are independently        H, OH, C₁₋₆ alkyl (preferably C₁₋₃ alkyl, more preferably CH₃),        C₁₋₆ hydroxyalkyl (preferably C₂₋₃ hydroxyalkyl, more preferably        —CH₂CH2OH), or C₁₋₆ alkyl (preferably C₁₋₃ alkyl, more        preferably CH₃) that is optionally substituted with        —N(R_(2d))(R_(2e)) wherein R_(2d) and R_(2e) are independently        H, OH, C₁₋₃ alkyl (preferably CH₃), or C₂₋₃ hydroxyalkyl        (preferably CH₂CH2OH), and wherein optionally R_(2b) and R_(2c)        together with the N they are both linked to may form a 3, 4, 5        or 6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and        morpholinyl), and wherein R_(2b) and R_(2c) are not both OH,        R_(2d) and R_(2e) are not both OH;-   R₃ is H; halo; C₁₋₃ alkyl; or C₁₋₃ alkoxy;-   R₄ and R₆ are independently H; halo (preferably F or Cl); N_(3;) C    ₁₋₃ alkyl (preferably CH₃); C₁₋₃ alkoxy (preferably OCH₃); or    —N(R_(2b))(R_(2c)) wherein R_(2b) and R_(2c) are independently H,    OH, CH₃, or ethyl, and optionally R_(2b) and R₂ together with the N    they are both linked to may form a 3, 4, 5 or 6-membered heterocycle    (e.g., piperidinyl, pyrrolidinyl, and morpholinyl), and wherein    R_(2b) and R_(2e) are not both OH;-   R₅ is H;-   R₇ and R₁₁ are independently H, halo (preferably F), CH₃, or OCH₃;-   R₈ and R₁₀ are independently H; halo (preferably F or Cl, more    preferably F); C₁₋₃ alkyl (preferably CH₃); C₁₋₃ alkoxy (preferably    OCH₃); and-   R₉ is selected from the group:    -   hydrogen; hydroxy; Cl; N₃;    -   C₁₋₃ alkyl (preferably methyl or ethyl) or C₁₋₃ haloalkyl        (preferably monofluoromethyl, difluoromethyl, trifluoromethyl);    -   —OR_(9a), wherein R_(9a) is C₁₋₃ alkyl (i.e., methyl, ethyl,        propyl, isopropyl) or C₁₋₃ haloalkyl (e.g., fluoroalkyl,        preferably fluoromethyl, i.e., CH₂F, CHF₂, CF₃);        —N(Ra)(Rb),wherein Ra and Rb are independently H, C1-3 alkyl, or        haloC1-3 alkyl; or    -   —COOR_(9b), wherein R_(9b) is C₁₋₃ alkyl (preferably methyl or        ethyl); and optionally R₉ and one of R₈ and R₁₀ together form a        3, 4, 5, or 6-membered carbocycle or heterocycle;    -   Q, T, U and V are independently C or N, wherein at least one of,        T, U and V are N, wherein when Q, T, U or V is nitrogen, then        the there is no substituent at the N; with the proviso that when        R₉ is H then R₈ and R₉ are not both H or one H and the other        alkyl. Preferably when R₉ is H then at least one of R₈ or R₁₀ is        not H or alkyl. More preferably when R₉ is H then at least one        of R₈ or R₁₀ is not H, alkyl, or halo.

In some specific embodiments, one or two of Q, T, U and V are N.

Preferably in this embodiment, when R₉ is H, R₈ or R₁₀ or both areindependently OH; Cl; N₃; C₁₋₃ haloalkyl (preferably monofluoromethyl,difluoromethyl, trifluoromethyl); —XR_(9a), where X is O or S, andR_(9a) is C₁₋₄ alkyl or C₁₋₃ haloalkyl (e.g., fluoroalkyl, preferablyfluoromethyl, i.e., CH₂F, CHF₂, CF₃); —NH(R^(a)) or —N(R^(a))(R^(b))where R^(a) and R^(b) are independently C₁₋₃ alkyl; or —COOR_(9b),wherein R_(9b) is C₁₋₃ alkyl (preferably methyl or ethyl). Morepreferably, when R₉ is H, R₈ or R₁₀ or both are independently N₃,—OR_(9a), wherein R_(9a) is C₁₋₄ alkyl or C₁₋₃ haloalkyl, or—N(R^(a))(R^(b)) where R^(a) and R^(b) are independently C₁₋₃ alkyl; or—COOR_(9b), wherein R_(9b) is C₁₋₃ alkyl (preferably methyl or ethyl).Even more preferably when R₉ is H, R₈ or R₁₀ or both are C₁₋₃ alkoxy orC₁₋₃ halo alkoxy.

Also preferably, when R₉ is C₁₋₆ alkyl or C₁₋₆ haloalkyl, R₂ is not Hand preferably R₂ is halo; C₁₋₃ alkyl optionally substituted with OH orhalo (preferably F, e.g., monofluoro, difluoro, or trifluoro); —XR_(2a)wherein X is S or O and R_(2a) is C₁₋₃ alkyl (preferably C₁₋₃ alkyl,more preferably CH₃) optionally substituted with halo (preferably F,e.g., monofluoro-, difluoro-, or trifluoro-substituted); or—N(R^(a))(R^(b)) wherein R^(a) and R^(b) are independently H, OH (R^(a)and R^(b) are not both OH), C₁₋₃ alkyl (preferably CH₃), C₂₋₃hydroxyalkyl. More preferably R₂ is methyl, ethyl, Cl, F, fluoromethyl(CH₂F, CHF₂, CF₃), C₁₋₃ hydroxyalkyl (preferably CH₂OH or CH₂CH₂OH),NH₂, NH₂OH, —NHCH₂CH₂OH, NHCH₃, N(CH₃)₂, N₃, morpholino, OCH₃, OC₂H₅, orSCH₃.

Also preferably, in this embodiment, when R₉ is H, R_(g) or R₁₀ or bothare OCH₃ and preferably R₇ and R₁₁ are H, and also preferably R₂ is nothydrogen and preferably R₂ is methyl or chloro. Also preferably in thisembodiment, when R₉ is alkyl or haloalkyl or chloro, R₂ is not hydrogenand preferably R₂ is methyl or chloro.

In another preferred embodiment, compounds of the invention includecompounds of Formula VIa or pharmaceutically acceptable salts orsolvates thereof, wherein:

-   R₁ is methyl or ethyl, preferably methyl;-   R₂ is H, methyl, ethyl, Cl, F, fluoromethyl (CH₂F, CHF₂, CF₃), C₁₋₃    hydroxyalkyl (preferably CH₂OH or CH₂CH₂OH), NH₂, NH₂OH,    —NHCH₂CH₂OH, NHCH₃, N(CH₃)₂, N₃, morpholino, OCH₃, OC₂H₅, or SCH₃;    R₃ is H, CH₃, OCH₃, F, or Cl; R₄ and R₆ are independently H, CH₃,    NH₂, N₃, F, or Cl; R₅ is H; R₇ and R₁₁ are independently H, F, or    OCH₃; R₈ and R₁₀ are independently H, F, Cl, or OCH₃; and-   R₉ is selected from the group:    -   hydrogen; hydroxy; Cl;    -   C₁₋₃ alkyl (preferably methyl or ethyl) or C₁₋₃ haloalkyl        (preferably monofluoromethyl, difluoromethyl, trifluoromethyl);    -   —OR_(9a), wherein R_(9a) is C₁₋₃ alkyl (i.e., methyl, ethyl,        propyl, isopropyl) or C₁₋₃ haloalkyl (e.g., fluoroalkyl,        preferably fluoromethyl, i.e., CH₂F, CHF₂, CF₃);    -   C₁₋₃ alkyl substituted amino (preferably —NHCH₃ or —N(CH₃)₂);    -   —N₃; or    -   —COOR_(9b), wherein R_(9b) is C₁₋₃ alkyl (preferably methyl or        ethyl), and optionally R₈ and R₉ together form a 3, 4, 5, or        6-membered carbocycle or heterocycle; and Q, T, U and V are        independently C or N, and at least one of Q, T, U and V is N,        wherein when Q, T, U or V is N, then there is no substituent at        the N. In some specific embodiments, one or two of Q, T, U and V        are nitrogen.

Preferably in this embodiment, when R₉ is H, R₈ or R₁₀ or both areindependently OH; Cl; N₃; C₁₋₃ haloalkyl (preferably monofluoromethyl,difluoromethyl, trifluoromethyl); —XR_(9a), where X is O or S, andR_(9a) is C₁₋₄ alkyl or C₁₋₃ haloalkyl (e.g., fluoroalkyl, preferablyfluoromethyl, i.e., CH₂F, CHF₂, CF₃); —NH(R^(a)) or —N(R^(a))(R^(b))where R^(a) and R^(b) are independently C₁₋₃ alkyl; or —COOR_(9b),wherein R_(9b) is C₁₋₃ alkyl (preferably methyl or ethyl). Morepreferably, when R₉ is H, R₈ or R₁₀ or both are independently N₃,—OR_(9a), wherein R_(9a) is C₁₋₄ alkyl or C₁₋₃ haloalkyl, or—N(R^(a))(R^(b)) where R^(a) and R^(b) are independently C₁₋₃ alkyl; or—COOR_(9b), wherein R_(9b) is C₁₋₃ alkyl (preferably methyl or ethyl).Even more preferably when R₉ is H, R₈ or R₁₀ or both are C₁₋₃ alkoxy orC₁₋₃ halo alkoxy.

Also preferably, when R₉ is C₁₋₆ alkyl or C₁₋₆ haloalkyl, R₂ is not Hand preferably R₂ is methyl, ethyl, Cl, F, fluoromethyl (CH₂F, CHF₂,CF₃), C₁₋₃ hydroxyalkyl (preferably CH₂OH or CH₂CH₂OH), NH₂, NH₂OH,—NHCH₂CH₂OH, NHCH₃, N(CH₃)₂, N₃, morpholino, OCH₃, OC₂H₅, or SCH₃.

Also preferably, in this embodiment, when R₉ is H, R₈ or R₁₀ or both areOCH₃ and preferably R₇ and R₁₁ are H, and also preferably R₂ is nothydrogen and preferably R₂ is methyl or chloro. Also preferably in thisembodiment, when R₉ is alkyl or haloalkyl or chloro, R₂ is not hydrogenand preferably R₂ is methyl or chloro.

In another preferred embodiment, compounds of the invention includecompounds of Formula VIa or pharmaceutically acceptable salts orsolvates thereof, wherein:

-   R₁ is methyl;-   R₂ is H, methyl, ethyl, Cl, F, fluoromethyl (CH₂F, CHF₂, CF₃),    CH₂OH, NH₂, NHCH₃, N(CH₃)₂, —NHCH₂CH₂OH, OCH₃, or SCH₃; R₃ is H,    CH₃, OCH₃, F, or Cl; R₄ and R₆ are independently H, CH₃, NH₂, F, or    Cl; R₅ is H; R₇ and R₁₁ are independently H, F, or OCH₃; R₈ and R₁₀    are independently H, F, Cl, or OCH₃; and-   R₉ is selected from the group:-   —OR_(9a), wherein R_(9a) is selected from the group of methyl,    ethyl, fluoromethyl (e.g., CH₂F, CHF₂, CF₃), and fluoroethyl;    -   —NHCH₃;    -   —N(CH₃)₂;    -   —N₃; and    -   —COOR_(9b), wherein R_(9b) is H or methyl or ethyl; and-   Q, T, U and V are independently C or N, and at least one of Q, T, U    and V is N, wherein when Q, T, U or V is N, then there is no    substituent at the N. In some specific embodiments, one or two of Q,    T, U and V are nitrogen.

In a more preferred embodiment, compounds of the invention includecompounds of Formula VIa or pharmaceutically acceptable salts orsolvates thereof, wherein:

-   R₁ is CH₃;-   R₂ is H, methyl, Cl, —CH₂OH, —NH₂, —NHCH₃, —NHCH₂CH₂OH, —OCH₃,    —SCH₃, or —CH₂F;-   R₃ is H, —CH₃, —OCH₃, or Cl;-   R₄ is H, CH₃, or NH₂;-   R₅ is H;-   R₆ is H, or CH₃;-   R₇ and R₁₁ are independently H, or F;-   R₈ and R₁₀ are independently H, or F or OCH₃;-   R₉ is —OCH₃ or —OC₂H₅, —N(CH₃)₂, —CO₂CH₃, —OCHF₂, or N₃; and-   Q, T, U and V are independently C or N, and at least one of Q, T, U    and V is N, wherein when Q, T, U or V is N, then there is no    substituent at the N. In some specific embodiments, one or two of Q,    T, U and V are nitrogen.

In a more preferred embodiment, the present invention provides compoundsof Formula VIa or pharmaceutically acceptable salts or solvates thereof,wherein R₁ is CH₃; R₂ is Cl, methyl, or CH₂F; R₃ is H, CH₃, F, or Cl;R₄, R₅ and R₆ are H; R₇, R₈, R₁₀ and R₁₁ are independently H or F; R₉ is—OCH₃ or —N(CH₃)₂; and Q, T, U and V are independently C or N, and atleast one of Q, T, U and V is N, wherein when Q, T, U or V is N, thenthere is no substituent at the N. In some specific embodiments, one ortwo of Q, T, U and V are nitrogen.

Other compounds of the invention include those of Formula VIb:

-   or pharmaceutically acceptable salts, or solvates thereof, wherein:-   R₁ is methyl or ethyl, preferably methyl;-   R₅ is H or F, preferably H; and-   R₂-R₄, R₆-R₁₁ are independently H, halo, N₃, OH, thiol, nitro, CN,    NH₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆    alkylthiol, halo-C₁₋₆ alkyl, C₂₋₆ alkenyl-O—, C₂₋₆ alkynyl-O—,    hydroxy-C₁₋₆ alkyl, C₁₋₆ alkoxy-C₁₋₆ alkyl, C₁₋₆ acyl, C₁₋₆ acyloxy,    —C₁₋₆ alkyl-C(O)O—C₁₋₆ alkyl, —C(O)O—C₁₋₆ alkyl, C₁₋₆    alkyl-C(O)O—C₁₋₆ alkyl, C₁₋₆ acylamido, N(R^(a))(R^(b)), —C₁₋₆    alkyl-C(O)N(R^(a))(R^(b)), —C(O)N(R^(a))(R^(b)),    N(R^(a))(R^(b))—C₁₋₆ alkyl-, 3, 4, 5, or 6-membered carbocycle,    heterocycle, aryl, or heteroaryl, wherein R^(a) and R^(b) are    independently H, OH (R^(a) and R^(b) are not both OH), C₂₋₆    hydroxyalkyl, or C₁₋₆ alkyl, or R^(a) and R^(b) together with the    nitrogen atom to which they are both linked form a 3, 4, 5 or    6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and    morpholinyl); wherein any of the groups is optionally substituted    with 1-3 substituents wherein each substituent is independently    halo, N₃, OH, thiol, nitro, CN, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆    alkynyl, C₁₋₆ alkoxy, C₁₋₆ alkylthiol, C₂₋₆ alkenyl-O—, C₂₋₆    alkynyl-O, hydroxy-C₁₋₆ alkyl, C₁₋₆ alkoxy-C₁₋₆ alkyl, C₁₋₆ acyl,    C₁₋₆ acyloxy, C₁₋₆ alkyl-C(O)O—C₁₋₆ alkyl, C₁₋₆ acylamido,    —N(R^(a))(R^(b)), —C₁₋₆ alkyl-C(O)N(R^(a))(R^(b)),    —C(O)N(R^(a))(R^(b)), N(R^(a))(R^(b))—C₁₋₆ alkyl-, wherein R^(a) and    R^(b) are independently H, OH (R^(a) and R^(b) are not both OH),    C₂₋₆ hydroxyalkyl, or C₁₋₆ alkyl or le and R^(b) together with the    nitrogen atom to which they are both linked form a 3, 4, 5 or    6-membered heterocycle, wherein optionally any two adjacent R₇-R₁₁    groups together form a 3, 4, 5 or 6-membered carbocycle or    heterocycle;-   provided that R₉ is not —O(C₁₋₆ alkyl)C(O)O(C₁₋₆ alkyl), and when R₉    is H then R₈ and R₁₀ are not both H or one H and the other halo.    Preferably when R₉ is H then R₈ and R₁₀ are not both H or one H and    the other halo or alkyl or haloalkyl.

In one embodiment, R₉ is selected from the group consisting of H, Cl,N₃,

C₁₋₆ alkyl (preferably C₁₋₃ alkyl, more preferably CH₃) optionallysubstituted with 1, 2 or 3 substituents, each substituent beingindependently OH, halo, C₁₋₃ alkoxy, (halo)C₁₋₃ alkoxy, —N(R^(a))(R^(b))where R^(a) and R^(b) are independently H, OH (R^(a) and R^(b) are notboth OH), C₂₋₄ hydroxyalkyl, or C₁₋₃ alkyl or R^(a) and R^(b) togetherwith the nitrogen atom to which they are both linked form a 3, 4, 5 or6-membered heterocycle;

—XR^(c) wherein X is S or O and R^(c) is C₁₋₆ alkyl (preferably C₁₋₃alkyl, more preferably CH₃) optionally substituted with with 1, 2 or 3substituents, each substituent being independently OH, halo, C₁₋₃alkoxy, or (halo)C₁₋₃ alkoxy;

—(C₀₋₃ alkyl)CO₂R^(d), wherein R^(d) is an C₁₋₆ alkyl, preferably C₁₋₃alkyl;

—N(R^(a))(R^(b)) where R^(a) and R^(b) are independently H, OH (R^(a)and R^(b) are not both OH), C₂₋₄ hydroxyalkyl, C₁₋₃ alkyl, or—N(R^(e))(R^(f)) where R^(e) and R^(f) are independently H, OH (R^(e)and R^(f) are not both OH), or C₁₋₃ alkyl; wherein optionally R^(a) andR^(b) together with the N form a 3, 4, 5 or 6-membered heterocycle, andoptionally R^(e) and R^(f) together with the nitrogen atom to which theyboth are linked form a 3, 4, 5 or 6-membered heterocycle; or

—(C₀₋₃ alkyl)C(O)N(R^(a))(R^(b)) where R^(a) and R^(b) are independentlyH or C₁₋₃ alkyl; and optionally R₉ and one of R₈ and R₁₀ together form a3, 4, 5, or 6-membered heterocycle. Preferably R₉ is selected from suchgroups except R₉ is not H or chloro.

In another embodiment, R₉ is H; OH; Cl; N₃; C₁₋₃ alkyl (preferablymethyl; C₁₋₃ haloalkyl (preferably monofluoromethyl, difluoromethyl,trifluoromethyl); —OR_(9a), wherein R_(9a) is C₁₋₄ alkyl or C₁₋₃haloalkyl (e.g., fluoroalkyl, preferably fluoromethyl, i.e., CH₂F, CHF₂,CF₃); —NH(R^(a)) or —N(R^(a))(R^(b)) where R^(a) and R^(b) areindependently C₁₋₃ alkyl; or —COOR_(9b), wherein R_(9b) is C₁₋₃ alkyl(preferably methyl or ethyl); and optionally R₉ and one of R₈ and R₁₀together form a 3, 4, 5, or 6-membered heterocycle. Preferably R₉ isselected from such groups except R₉ is not H or chloro.

In a preferred embodiment, R₉ is N₃; —OR_(9a), wherein R_(9a) is C₁₋₃alkyl optionally substituted with 1-7 F; —N(R^(a))(R^(b)) where R^(a)and R^(b) are independently C₁₋₃ alkyl; or —COOR_(9b) where R_(9b) isC₁₋₃ alkyl.

In more preferred embodiment, R₉ is —OCH₃, —OC₂H₅, —N(CH₃)₂, —CO₂CH₃,—OCHF₂, or N₃.

Preferably when R₉ is H, R₈ or R₁₀ or both are independently OH; N₃;—XR_(9a), where X is O or S, and R_(9a) is C₁₋₄ alkyl or C₁₋₃ haloalkyl(e.g., fluoroalkyl, preferably fluoromethyl, i.e., CH₂F, CHF₂, CF₃);—NH(R^(a)) or —N(R^(a))(R^(b)) where R^(a) and R^(b) are independentlyC₁₋₃ alkyl; or —COOR_(9b), wherein R_(9b) is C₁₋₃ alkyl (preferablymethyl or ethyl). More preferably, when R₉ is H, R₈ or R₁₀ or both areindependently N₃, —OR_(9a), wherein R_(9a) is C₁₋₄ alkyl or C₁₋₃haloalkyl, or —N(R^(a))(R^(b)) where R^(a) and R^(b) are independentlyC₁₋₃ alkyl; or —COOR_(9b), wherein R_(9b) is C₁₋₃ alkyl (preferablymethyl or ethyl). Even more preferably when R₉ is H, R₈ or R₁₀ or bothare C₁₋₃ alkoxy or C₁₋₃ halo alkoxy.

Also preferably in the various embodiments, when R₉ is H, R₈ and R10 arenot H or one H and the other halo, and R2 is not H, and preferably R₂ isis halo; N₃, C₁₋₃ alkyl optionally substituted with OH or halo(preferably F, e.g., monofluoro, difluoro, or trifluoro); —XR_(2a)wherein X is S or O and R_(2a) is C₁₋₃ alkyl (more preferably CH₃)optionally substituted with halo (preferably F, e.g., monofluoro-,difluoro-, or trifluoro-substituted); or —N(R^(a))(R^(b)) wherein R^(a)and R^(b) are independently H, OH (R^(a) and R^(b) are not both OH),C₁₋₃ alkyl (preferably CH₃), C₂₋₃ hydroxyalkyl. More preferably R₂ ismethyl, ethyl, Cl, F, fluoromethyl (CH₂F, CHF₂, CF₃), C₁₋₃ hydroxyalkyl(preferably CH₂OH or CH₂CH₂OH), NH₂, NH₂OH, —NHCH₂CH₂OH, NHCH₃, N(CH₃)₂,N₃, morpholino, OCH₃, OC₂H₅, or SCH₃.

Also preferably, when R₉ is C₁₋₆ alkyl, halo, or C₁₋₆ haloalkyl, R₂ isnot H, and preferably R₂ is halo; N₃, C₁₋₃ alkyl optionally substitutedwith OH or halo (preferably F, e.g., monofluoro, difluoro, ortrifluoro); —XR_(2a) wherein X is S or O and R_(2a) is C₁₋₃ alkyl (morepreferably CH₃) optionally substituted with halo (preferably F, e.g.,monofluoro-, difluoro-, or trifluoro-substituted); or —N(R^(a))(R^(b))wherein R^(a) and R^(b) are independently H, OH (R^(a) and R^(b) are notboth OH), C₁₋₃ alkyl (preferably CH₃), C₂₋₃ hydroxyalkyl. Morepreferably R₂ is methyl, ethyl, Cl, F, fluoromethyl (CH₂F, CHF₂, CF₃),C₁₋₃ hydroxyalkyl (preferably CH₂OH or CH₂CH₂OH), NH₂, NH₂OH,—NHCH₂CH₂OH, NHCH₃, N(CH₃)₂, N₃, morpholino, OCH₃, OC₂H₅, or SCH₃.

In one embodiment, R₂ is H; halo; N₃; C₁₋₆ alkyl (preferably C₁₋₃ alkyl,more preferably CH₃) optionally substituted with OH or halo (preferablyF, e.g., monofluoro, difluoro, or trifluoro); —XR_(2a) wherein X is S orO, and R_(2a) is C₁₋₆ alkyl (preferably C₁₋₃ alkyl, more preferably CH₃)optionally substituted with OH or halo (preferably F, e.g., monofluoro-,difluoro-, or trifluoro-substituted); —CO₂R^(d), wherein R^(d) is C₁₋₃alkyl, preferably methyl or ethyl; or —N(R^(a))(R^(b)) wherein R^(a) andR^(b) are independently H, OH (R^(a) and R^(b) are not both OH), C₁₋₃alkyl (preferably CH₃), C₁₋₆ hydroxyalkyl (preferably C₂₋₃ hydroxyalkyl,more preferably —CH₂CH₂OH), or C₁₋₆ alkyl (preferably C₁₋₃ alkyl, morepreferably CH₃) that is optionally substituted with —N(R^(e))(R^(f))wherein R^(e) and R^(f) are independently H, OH (R^(e) and R^(f) are notboth OH), C₁₋₃ alkyl (preferably CH₃), or C₂₋₃ hydroxyalkyl (preferably—CH₂CH2OH), and wherein optionally R^(a) and R^(b) together with thenitrogen they both are linked to may form a 3, 4, 5 or 6-memberedheterocycle.

In a preferred embodiment, R₂ is H; halo; C₁₋₃ alkyl optionallysubstituted with OH or halo (preferably F, e.g., monofluoro, difluoro,or trifluoro); —XR_(2a) wherein X is S or O and R_(2a) is C₁₋₃ alkyl(preferably C₁₋₃ alkyl, more preferably CH₃) optionally substituted withhalo (preferably F, e.g., monofluoro-, difluoro-, ortrifluoro-substituted); or —N(R^(a))(R^(b)) wherein R^(a) and R^(b) areindependently H, OH (R^(a) and R^(b) are not both OH), C₁₋₃ alkyl(preferably CH₃), C₂₋₃ hydroxyalkyl.

In preferred embodiments, R₂ is H, methyl, ethyl, Cl, F, fluoromethyl(CH₂F, CHF₂, CF₃), C₁₋₃ hydroxyalkyl (preferably CH₂OH or CH₂CH₂OH),NH₂, NH₂OH, —NHCH₂CH₂OH, NHCH₃, N(CH₃)₂, N₃, morpholino, OCH₃, OC₂H₅, orSCH₃.

In more preferred embodiments, R₂ is H, methyl, Cl, —CH₂OH, —NH₂,—NHCH₃, —NHCH₂CH₂OH, —OCH₃, —SCH₃, or —CH₂F.

In one embodiment, compounds of the invention include compounds ofFormula VIb or pharmaceutically acceptable salts or solvates thereof,wherein:

-   R₁ is methyl or ethyl, preferably methyl;-   R₂ is H; halo; N₃;    -   C₁₋₆ alkyl (preferably C₁₋₃ alkyl, more preferably CH₃)        optionally substituted with OH or halo (preferably F, e.g.,        monofluoro, difluoro, or trifluoro);    -   —XR_(2a) wherein X is S or O, and R_(2a) is C₁₋₆ alkyl        (preferably C₁₋₃ alkyl, more preferably CH₃) optionally        substituted with OH or halo (preferably F, e.g., monofluoro-,        difluoro-, or trifluoro-substituted);    -   —CO₂R^(d), wherein R^(d) is C₁₋₃ alkyl, preferably methyl or        ethyl; or    -   —N(R^(a))(R^(b)) wherein R^(a) and R^(b) are independently H, OH        (R^(a) and R^(b) are not both OH), C₁₋₃ alkyl (preferably CH₃),        C₁₋₆ hydroxyalkyl (preferably C₂₋₃ hydroxyalkyl, more preferably        CH₂CH₂OH), or C₁₋₆ alkyl (preferably C₁₋₃ alkyl, more preferably        CH₃) that is optionally substituted with —N(R^(e))(R^(f))        wherein R^(e) and R^(f) are independently H, OH (R^(e) and R^(f)        are not both OH), C₁₋₃ alkyl (preferably CH₃), or C₂₋₃        hydroxyalkyl (preferably —CH₂CH2OH), and wherein optionally        R^(a) and R^(b) together may form a 3, 4, 5 or 6-membered        heterocycle (e.g., piperidinyl, pyrrolidinyl, and morpholinyl);-   R₃ is H; halo; C₁₋₃ alkyl; or C₁₋₃ alkoxy;-   R₄ and R₆ are independently H; halo (preferably F or Cl); N₃; C₁₋₆    alkyl (preferably C₁₋₃, more preferably CH₃); C₁₋₃ alkoxy    (preferably OCH₃); or —N(R_(2b))(R_(2c)) wherein R_(2b) and R_(2c)    are independently H, OH, C₁₋₆ alkyl (preferably C₁₋₃ alkyl, more    preferably CH₃), C₁₋₆ hydroxyalkyl (preferably C₂₋₃ hydroxyalkyl,    more preferably —CH₂CH2OH), or C₁₋₆ alkyl (preferably C₁₋₃ alkyl,    more preferably CH₃) that is optionally substituted with    —N(R_(2d))(R_(2e)) wherein R_(2d) and R₂, are independently H, OH,    C₁₋₃ alkyl (preferably CH₃) or C₂₋₃ hydroxyalkyl (preferably    —CH₂CH2OH), wherein R_(2b) and R₂ together may form a 3, 4, 5 or    6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and    morpholinyl), and wherein R_(2b) and R₂ are not both OH, R_(2d) and    R₂, are not both OH;-   R₅ is H or F, preferably H;-   R₇ and R₁₁ are independently H; halo (preferably F or Cl, more    preferably F); CH₃; or OCH₃;-   R₈ and R₁₀ are independently H; halo (preferably F or Cl, more    preferably Cl); OH; N₃; C₁₋₃ alkyl (preferably CH₃); C₁₋₃ alkoxy    (preferably OCH₃); C₁₋₃ haloalkyl (preferably monofluoromethyl,    difluoromethyl, trifluoromethyl); —XR_(9a), where X is O or S, and    R_(9a) is C₁₋₄ alkyl or C₁₋₃ haloalkyl (e.g., fluoroalkyl,    preferably fluoromethyl, i.e., CH₂F, CHF₂, CF₃); —NH(R^(a)) or    —N(R^(a))(R^(b)) where R^(a) and R^(b) are independently C₁₋₃ alkyl;    or —COOR_(9b), wherein R_(9b) is C₁₋₃ alkyl (preferably methyl or    ethyl). and-   R₉ is H; OH; N₃; halo;    -   C₁₋₃ alkyl (preferably methyl or ethyl) or C₁₋₃ haloalkyl        (preferably monofluoromethyl, difluoromethyl, trifluoromethyl);    -   —(C₀₋₃ alkyl)C(O)N(R^(a))(R^(b)) where R^(a) and R^(b) are        independently H, C₂₋₄ hydroxyalkyl, C₁₋₃ alkyl, or or C₁₋₃ alkyl        optionally substituted with —N(R^(e))(R^(f)) where R^(e) and        R^(f) are independently H, OH (R^(a) and R^(b) are not both OH),        or C₁₋₃ alkyl; wherein optionally R^(a) and R^(b) together with        the N form a 3, 4, 5 or 6-membered heterocycle, and optionally        R^(e) and R^(f) together with the nitrogen atom to which they        both are linked form a 3, 4, 5 or 6-membered heterocycle;    -   —CO₂—R_(2f), wherein R_(2f) is an optionally substituted C₁₋₆        alkyl (preferably C₁₋₃ alkyl, more preferably methyl or ethyl),        the alkyl may be optionally substituted with OH, halo, C₁₋₃        alkoxy, amino, and C₁₋₃ alkylamino;    -   —XR_(2a) wherein X is S or O and R_(2a) is C₁₋₆ alkyl        (preferably C₁₋₃ alkyl, more preferably CH₃) optionally        substituted with a moiety selected from the group OH, halo, C₁₋₃        alkoxy, amino, and C₁₋₃ alkylamino; or    -   —N(R_(2b))(R_(2c)) wherein R_(2b) and R_(2c) are independently        H, OH, C₁₋₆ alkyl (preferably C₁₋₃ alkyl, more preferably CH₃),        C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl (preferably C₂₋₃ hydroxyalkyl,        more preferably —CH₂CH2OH), or C₁₋₆ alkyl (preferably C₁₋₃        alkyl, more preferably CH₃) that is optionally substituted with        —N(R_(2d))(R_(2e)) wherein R_(2d) and R_(2e) are independently        H, OH, C₁₋₃ alkyl (preferably CH₃) or C₂₋₃ hydroxyalkyl        (preferably —CH₂CH2OH), wherein optionally R_(2b) and R₂        together with the nitrogen they both are linked to may form a 3,        4, 5 or 6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl,        and morpholinyl), and wherein R_(2b) and R₂ are not both OH,        R_(2d) and R₂, are not both OH; optionally, R₉ and one of R₈ and        R₁₀ together form a 3, 4, 5 or 6-membered carbocycle or        heterocycle;        provided that when R₉ is H then R₈ and R₁₀ are not both H or one        H and the other halo.

Preferably when R₉ is H, R₈ or R₁₀ or both are independently OH; N₃;—XR_(9a), where X is O or S, and R_(9a) is C₁₋₄ alkyl or C₁₋₃ haloalkyl(e.g., fluoroalkyl, preferably fluoromethyl, i.e., CH₂F, CHF ₂, CF₃);—NH(R^(a)) or —N(R^(a))(R^(b)) where R^(a) and R^(b) are independentlyC₁₋₃ alkyl; or —COOR_(9b), wherein R_(9b) is C₁₋₃ alkyl (preferablymethyl or ethyl). More preferably, when R₉ is H, R₈ or R₁₀ or both areindependently N₃, —OR_(9a), wherein R_(9a) is C₁₋₄ alkyl or C₁₋₃haloalkyl, or —N(R^(a))(R^(b)) where R^(a) and R^(b) are independentlyC₁₋₃ alkyl; or —COOR_(9b), wherein R_(9b) is C₁₋₃ alkyl (preferablymethyl or ethyl). Even more preferably when R₉ is H, R₈ or R₁₀ or bothare C₁₋₃ alkoxy or C₁₋₃ halo alkoxy.

Also preferably, when R₉ is C₁₋₆ alkyl, halo, or C₁₋₆ haloalkyl, then R₂is is not H and preferably R₂ is methyl, ethyl, Cl, F, fluoromethyl(CH₂F, CHF₂, CF₃), C₁₋₃ hydroxyalkyl (preferably CH₂OH or CH₂CH₂OH),NH₂, NH₂OH, —NHCH₂CH₂OH, NHCH₃, N(CH₃)₂, N₃, morpholino, OCH₃, OC₂H₅, orSCH₃.

In another preferred embodiment, compounds of the invention includecompounds of Formula VIb or pharmaceutically acceptable salts orsolvates thereof, wherein:

-   R₁ is methyl or ethyl, and preferably methyl;-   R₂ is H; halo; N₃;    -   C₁₋₆ alkyl (preferably C₁₋₃ alkyl, more preferably CH₃)        optionally substituted with 1-4 substituents which are        independently OH or halo (preferably F, e.g., monofluoro,        difluoro, or trifluoro);    -   —XR_(2a) wherein X is S or O, and R_(2a) is C₁₋₆ alkyl        (preferably C₁₋₃ alkyl, more preferably CH₃) optionally        substituted with OH or halo (preferably F, e.g., monofluoro-,        difluoro-, or trifluoro-substituted);    -   —CO₂—R_(2f), wherein R_(2f) is C₁₋₆ (preferably C₁₋₃, more        preferably methyl or ethyl); or    -   —N(R_(2b))(R_(2c)) wherein R_(2b) and R₂ are independently H,        OH, C₁₋₆ alkyl (preferably C₁₋₃ alkyl, more preferably CH₃),        C₁₋₆ hydroxyalkyl (preferably C₂₋₃ hydroxyalkyl, more preferably        —CH₂CH2OH), or C₁₋₆ alkyl (preferably C₁₋₃ alkyl, more        preferably CH₃) that is optionally substituted with        —N(R_(2d))(R_(2e)) wherein R_(2d) and R_(2e) are independently        H, OH, C₁₋₃ alkyl (preferably CH₃), or C₂₋₃ hydroxyalkyl        (preferably —CH₂CH₂OH), and wherein optionally R_(2b) and R_(2e)        together with the nitrogen they both are linked to may form a 3,        4, 5 or 6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl,        and morpholinyl), and wherein R_(2b) and R_(2c) are not both OH,        R_(2d) and R_(2e) are not both OH;-   R₃ is H; halo; C₁₋₃ alkyl; or C₁₋₃ alkoxy;-   R₄ and R₆ are independently H; halo (preferably F or Cl); N_(3;)    C₁₋₃ alkyl (preferably CH₃); C₁₋₃ alkoxy (preferably OCH₃); or    —N(R_(2b))(R_(2c)) wherein R_(2b) and R_(2e) are independently H,    OH, CH₃, and optionally R_(2b) and R_(2e) together with the nitrogen    they both are linked to may form a 3, 4, 5 or 6-membered heterocycle    (e.g., piperidinyl, pyrrolidinyl, and morpholinyl), and wherein    R_(2b) and R_(2c) are not both OH;-   R₅ is H;-   R₇ and R₁₁ are independently H, halo (preferably F), CH₃, or OCH₃;-   R₈ and R₁₀ are independently H; halo (preferably F or Cl, more    preferably F); C₁₋₃ alkyl (preferably CH₃); C₁₋₃ alkoxy (preferably    OCH₃); —XR_(9a), where X is O or S, and R_(9a) is C₁₋₄ alkyl or C₁₋₃    haloalkyl (e.g., fluoroalkyl, preferably fluoromethyl, i.e., CH₂F,    CHF₂, CF₃); —N(R^(a))(R^(b)) where R^(a) and R^(b) are independently    C₁₋₃ alkyl; or —COOR_(9b), wherein R_(9b) is C₁₋₃ alkyl (preferably    methyl or ethyl); and-   R₉ is selected from the group: hydrogen; hydroxy; N₃;    -   C₁₋₃ alkyl (preferably methyl or ethyl) or C₁₋₃ haloalkyl        (preferably monofluoromethyl, difluoromethyl, trifluoromethyl);    -   —OR_(9a), wherein R_(9a) is C₁₋₃ alkyl (i.e., methyl, ethyl,        propyl, isopropyl) or C₁₋₃ haloalkyl (e.g., fluoroalkyl,        preferably fluoromethyl, i.e., CH₂F, CHF₂, CF₃);    -   —N(R_(2b))(R_(2c)) wherein R_(2b) and R_(2c) are independently        H, C₁₋₃ alkyl, or C₁₋₃ haloalkyl;or    -   —COOR_(9b), wherein R_(9b) is C₁₋₃ alkyl (preferably methyl or        ethyl); and optionally R₉ and one of R₈ and R₁₀ together form a        3, 4, 5, or 6-membered hetercycle;        provided that when R₉ is H at least one of R₈ and R₁₀ is not H        or halo, preferably at least one of R₈ and R₁₀ is not H or halo        or C₁₋₃ alkyl.

Preferably in this embodiment, when R₉ is H, R₈ or R₁₀ or both areindependently —XR_(9a), where X is O or S, and R_(9a) is C₁₋₄ alkyl orC₁₋₃ haloalkyl (e.g., fluoroalkyl, preferably fluoromethyl, i.e., CH₂F,CHF₂, CF₃); —N(R^(a))(R^(b)) where R^(a) and R^(b) are independentlyC₁₋₃ alkyl; or —COOR_(9b), wherein R_(9b) is C₁₋₃ alkyl (preferablymethyl or ethyl). More preferably, when R₉ is H, R₈ or R₁₀ or both areindependently N₃, —OR_(9a), wherein R_(9a) is C₁₋₄ alkyl or C₁₋₃haloalkyl, or —N(R^(a))(R^(b)) where R^(a) and R^(b) are independentlyC₁₋₃ alkyl; or —COOR_(9b), wherein R_(9b) is C₁₋₃ alkyl (preferablymethyl or ethyl). Even more preferably when R₉ is H, R₈ or R₁₀ or bothare C₁₋₃ alkoxy or C₁₋₃ halo alkoxy.

Also preferably in this embodiment, when R₉ is H then R₈ and R₁₀ are notboth H or one H and the other halo, and R₂ is not H.

Also preferably, in this embodiment, when R₉ is C₁₋₆ alkyl, halo, orC₁₋₆ haloalkyl, then R₂ is not H and preferably R₂ is methyl, ethyl, Cl,F, fluoromethyl (CH₂F, CHF₂, CF₃), C₁₋₃ hydroxyalkyl (preferably CH₂OHor CH₂CH₂OH), NH₂, NH₂OH, —NHCH₂CH₂OH, NHCH₃, N(CH₃)₂, N₃, morpholino,OCH₃, OC₂H₅, or SCH₃.

Also preferably, in this embodiment, when R₉ is H, R₈ or R₁₀ or both areOCH₃ and preferably R₇ and R₁₁ are H, and also preferably R₂ is nothydrogen and preferably R₂ is methyl or chloro. Also preferably in thisembodiment, when R₉ is alkyl or haloalkyl or chloro, R₂ is not hydrogenand preferably R₂ is methyl or chloro.

In another preferred embodiment, compounds of the invention includecompounds of Formula VIb or pharmaceutically acceptable salts orsolvates thereof, wherein:

-   R₁ is methyl or ethyl, and preferably methyl;-   R₂ is H; halo; N₃;    -   C₁₋₆ alkyl (preferably C₁₋₃ alkyl, more preferably CH₃)        optionally substituted with 1-4 substituents which are OH or        halo (preferably F, e.g., monofluoro, difluoro, or trifluoro);    -   —XR_(2a) wherein X is S or O, and R_(2a) is C₁₋₆ alkyl        (preferably C₁₋₃ alkyl, more preferably CH₃) optionally        substituted with OH or halo (preferably F, e.g., monofluoro-,        difluoro-, or trifluoro-substituted); or    -   —N(R_(2b))(R_(2c)) wherein R_(2b) and R₂ are independently H,        OH, C₁₋₆ alkyl (preferably C₁₋₃ alkyl), C₁₋₆ hydroxyalkyl        (preferably C₂₋₃ hydroxyalkyl, more preferably CH₂CH2OH), or        R_(2b) and R_(2c) together form a 3, 4, 5 or 6-membered        heterocycle (e.g., piperidinyl, pyrrolidinyl, and morpholinyl);-   R₃ is H; halo; C₁₋₃ alkyl; or C₁₋₃ alkoxy;-   R₄ and R₆ are independently H; halo (preferably F or CO; N_(3;) C₁₋₃    alkyl (preferably CH₃); C₁₋₃ alkoxy (preferably OCH₃); or    —N(R_(2b))(R_(2c)) wherein R_(2b) and R₂ are independently H, OH    (R_(2b) and R_(2c) are not both OH), CH₃, or R_(2b) and R₂ together    form a 3, 4, 5 or 6-membered heterocycle (e.g., piperidinyl,    pyrrolidinyl, and morpholinyl);-   R₅ is H or F, preferably H;-   R₇ and R₁₁ are independently H, halo (preferably F), C₁₋₃ alkyl    (preferably CH₃), C₁₋₃ alkoxy (preferably OCH₃), or C₁₋₃ alkylthiol;    Preferably R₇ and R₁₁ are independently H, halo or methoxy;-   R₈ and R₁₀ are independently H; halo (preferably F or CO; C₁₋₃ alkyl    (preferably CH₃); C₁₋₃ alkoxy (preferably OCH₃) or C₁₋₃ alkylthiol;    and-   R₉ is selected from the group:    -   hydrogen; hydroxy; Cl; N₃;    -   C₁₋₃ alkyl (preferably methyl or ethyl) or C₁₋₃ haloalkyl        (preferably monofluoromethyl, difluoromethyl, trifluoromethyl);    -   —OR_(9a), wherein R₁₂ is C₁₋₃ alkyl (i.e., methyl, ethyl,        propyl, isopropyl) or C₁₋₃ haloalkyl (e.g., fluoroalkyl,        preferably fluoromethyl, i.e., CH₂F, CHF₂, CF₃);    -   —N(R_(2b))(R_(2c)) wherein R_(2b) and R₂ are independently C₁₋₃        alkyl;or    -   —COOR_(9b), wherein R_(9b) is C₁₋₃ alkyl (preferably methyl or        ethyl); and optionally R₉ and one of R₈ and R₁₀ together form a        3, 4, 5, or 6-membered heterocycle;        provided that when R₉ is H at least one of R₈ and R₁₀ is not H        or halo, preferably at least one of R₈ and R₁₀ is not H or halo        or C₁₋₃ alkyl.

Preferably in this embodiment, when R₉ is H, R₈ or R₁₀ or both areindependently C₁₋₃ alkoxy (preferably OCH₃) or C₁₋₃ alkylthiol, eachbeing optionally substituted with 1-4 F. Even more preferably when R₉ isH, R₈ or R₁₀ or both are methoxy or ethoxy. Also preferably R₂ is not H.

Also preferably, when R₉ is C₁₋₃ alkyl, halo, or C₁₋₃ haloalkyl, then R₂is not H, preferably R₂ is methyl, ethyl, Cl, F, fluoromethyl (CH₂F,CHF₂, CF₃), C ₁₋₃ hydroxyalkyl (preferably CH₂OH or CH₂CH₂OH), NH₂,NH₂OH, —NHCH₂CH₂OH, NHCH₃, N(CH₃)₂, N₃, morpholino, OCH₃, OC₂H₅, orSCH₃.

Also preferably, in this embodiment, when R₉ is H, R₈ or R₁₀ or both areOCH₃ and preferably R₇ and R₁₁ are H, and also preferably R₂ is nothydrogen and preferably R₂ is methyl or chloro. Also preferably in thisembodiment, when R₉ is alkyl or haloalkyl or chloro, R₂ is not hydrogenand preferably R₂ is methyl or chloro.

In another preferred embodiment, compounds of the invention includecompounds of Formula VIb or pharmaceutically acceptable salts orsolvates thereof, wherein:

-   R₁ is methyl or ethyl, preferably methyl;-   R₂ is H, methyl, ethyl, Cl, F, fluoromethyl (CH₂F, CHF₂, CF₃), C₁₋₃    hydroxyalkyl (preferably CH₂OH or CH₂CH₂OH), NH₂, NH₂OH,    —NHCH₂CH₂OH, NHCH₃, N(CH₃)₂, N₃, morpholino, OCH₃, OC₂H₅, or SCH₃;    R₃ is H, CH₃, OCH₃, F, or Cl; R₄ and R₆ are independently H, CH₃,    NH₂, N₃, F, or Cl; R₅ is H; R₇ and R₁₁ are independently H, F, or    OCH₃; R₈ and R₁₀ are independently H, F, Cl, or OCH₃; and-   R₉ is selected from the group:    -   H; OH; N₃;    -   C₁₋₃ alkyl (preferably methyl or ethyl) or C₁₋₃ haloalkyl        (preferably monofluoromethyl, difluoromethyl, trifluoromethyl);    -   —OR_(9a), wherein R_(9a) is C₁₋₃ alkyl (i.e., methyl, ethyl,        propyl, isopropyl) or C₁₋₃ haloalkyl (e.g., fluoroalkyl,        preferably fluoromethyl, i.e., CH₂F, CHF₂, CF₃);    -   —N(R_(2b))(R_(2c)) wherein R_(2b) and R₂ are independently C₁₋₃        alkyl; or    -   —COOR_(9b), wherein R_(9b) is C₁₋₃ alkyl (preferably methyl or        ethyl), and optionally R₈ and R₉ together form a 3, 4, 5, or        6-membered heterocycle; provided that when R₉ is H, at least one        of R₈ and R₁₀ is OCH₃, and when R₉ is C₁₋₃ alkyl or C₁₋₃        haloalkyl or Cl then R₂ is Cl or methyl or ethyl.

Preferably in this embodiment, when R₉ is H, R₈ or R₁₀ or both areindependently C₁₋₃ alkoxy (preferably OCH₃) or C₁₋₃ alkylthiol, eachbeing optionally substituted with 1-4 F. Even more preferably when R₉ isH, R₈ or R₁₀ or both are methoxy or ethoxy. Also preferably R₂ is not H.

Also preferably, when R₉ is C₁₋₃ alkyl, halo, or C₁₋₃ haloalkyl, then R₂is not H, preferably R₂ is methyl, ethyl, Cl, F, fluoromethyl (CH₂F,CHF₂, CF₃), C₁₋₃ hydroxyalkyl (preferably CH₂OH or CH₂CH₂OH), NH₂,NH₂OH, —NHCH₂CH₂OH, NHCH₃, N(CH₃)₂, N₃, morpholino, OCH₃, OC₂H₅, orSCH₃.

Also preferably, in this embodiment, when R₉ is H, R₈ or R₁₀ or both areOCH₃ and preferably R₇ and R₁₁ are H, and also preferably R₂ is nothydrogen and preferably R₂ is methyl or chloro. Also preferably in thisembodiment, when R₉ is alkyl or haloalkyl or chloro, R₂ is not hydrogenand preferably R₂ is methyl or chloro.

In another preferred embodiment, compounds of the invention includecompounds of Formula VIb or pharmaceutically acceptable salts orsolvates thereof, wherein:

-   R₁ is CH₃;-   R₂ is H, methyl, ethyl, Cl, F, fluoromethyl (CH₂F, CHF₂, CF₃),    CH₂OH, NH₂, NHCH₃, N(CH₃)₂, —NHCH₂CH₂OH, OCH₃, or SCH₃; R₃ is H,    CH₃, OCH₃, F, or Cl; R₄ and R₆ are independently H, CH₃, NH₂, F, or    Cl; R₅ is H; R₇ and R₁₁ are independently H, F, or OCH₃; R₈ and R₁₀    are independently H, F, Cl, or OCH₃; and-   R₉ is selected from the group:-   —OR₁₂, wherein R₁₂ is selected from the group of methyl, ethyl,    fluoromethyl (e.g., CH₂F, CHF₂, CF₃), and fluoroethyl;    -   —NHCH₃;    -   —N(CH₃)₂;    -   —N₃; and    -   —COOR_(D), wherein R₁₃ is methyl or ethyl.

In a more preferred embodiment, compounds of the invention includecompounds of Formula VIb or pharmaceutically acceptable salts orsolvates thereof, wherein:

-   R₁ is CH₃;-   R₂ is H, methyl, Cl, —CH₂OH, —NH₂, —NHCH₃, —NHCH₂CH₂OH, —OCH₃,    —SCH₃, or —CH₂F;-   R₃ is H, —CH₃, —OCH₃, or Cl;-   R₄ is H, CH₃, or NH₂;-   R₅ is H;-   R₆ is H, or CH₃;-   R₇ and R₁₁ are independently H, or F;-   R₈ and R₁₀ are independently H, or F or OCH₃; and-   R₉ is —OCH₃ or —OC₂H₅, —N(CH₃)₂, —CO₂CH₃, —OCHF₂, or N₃.

In a more preferred embodiment, the present invention provides compoundsof Formula VIb or pharmaceutically acceptable salts or solvates thereof,wherein R₁ is CH₃; R₂ is Cl, methyl, or CH₂F; R₃ is H, CH₃, F, or Cl;R₄, R₅ and R₆ are H; R₇, R₈, R₁₀ and R₁₁ are independently H or F; andR₉ is —OCH₃ or —N(CH₃)₂.

In another embodiment, compounds of Formula VIb include compoundswherein:

-   R₁ is methyl or ethyl;-   R₂ is methyl, ethyl, fluoromethyl, trifluoromethyl, methoxy, chloro,    hydrogen, morpholino, hydroxymethane, methylthiol, or an amino    optionally substituted with hydroxyethyl, or hydroxy;-   R₃ is hydrogen, chloro, methyl, or methoxy;-   R₄ and R₆ are independently hydrogen, chloro, or methyl;-   R₅ is hydrogen;-   R₇, R₈, R₁₀, and R₁₁ are independently hydrogen, fluoro, methyl, or    methoxy; and R₉ is methyl, ethyl, methoxy, ethoxy, propoxy,    isopropoxy, trifluoromethoxy, difluoromethoxy, azido, dimethylamino,    methylcarboxy, chloro, hydrogen, or hydroxyl; or pharmaceutically    acceptable salts or solvates thereof.

Preferably, the compounds of this embodiment are not selected form thegroup consisting of:

-   6-amino-4-[(N-methyl-N-phenyl)amino]quinazoline;    -   1-{4-[(N-methyl-N-phenyl)amino]-6-quinazolinyl}-3-methyltriazene;    -   1-{4-[(N-methyl-N-phenyl)amino]-6-quinazolinyl}-3,3-dimethyltriazene;-   4-(N-methylanilino)-6-sulfonylquinazoline;-   4-(N-methylanilino)-6-halosulfonylquinazoline;-   8-Chloro-4-(N-methylanilino)quinazoline;-   4-(N-methylanilino)-8-trifluoromethylquinazoline;-   2-butyl-N-methyl-N-phenylquinazolin-4-amine;    -   4-(N-methylanilino)-6,8-dimethylquinazoline;-   4-(N-methylanilino)-quinazoline;-   4-(N-methylanilino)-6-methoxyquinazoline;-   4-(N-methylanilino)-6-chloroquinazoline;-   N-(3-chlorophenyl)-N-(quinazolin-4-yl)-N-methyl-amine;-   4-(N-methylanilino)-2-chloroquinazoline;-   4-(N-methylanilino)-2-chloro-8-methoxyquinazoline;-   4-(N-ethylanilino)-2-chloroquinazoline;-   4-(N-methylanilino)-2-chloro-6-methoxyquinazoline;-   4-(N-methylanilino)-2-chloro-8-fluoroquinazoline;-   2-amino-4-(N-methylphenylamino)quinazoline hydrochloride; or-   2-amino-4-(N-methylphenylamino)-8-methoxyquinazoline hydrochloride.

In another embodiment, compounds of Formula VIb include compoundswherein:

-   R₁ is methyl;-   R₂ is methyl, chloro, fluoromethyl, hydroxymethyl, amino, hydrogen,    or hydroxyethylamino;-   R₃ is hydrogen, methyl, methoxy, or chloro;-   R₄ and R₆ are independently hydrogen or methyl;-   R₅ is hydrogen;-   R₇ and R₁₁ are independently hydrogen or fluoro;-   R₈ and R₁₀ are independently hydrogen or fluoro; and-   R₉ is methoxy, ethoxy, dimethylamino, methylcarboxy,    difluoromethoxy, or azido; or pharmaceutically acceptable salts or    solvates thereof.

Among all the compounds of the present invention as disclosed above,preferred are those that can induce caspase activation as determined bythe method and under conditions (measurement at 24 hours) described inExample 143, preferably at an EC₅₀ of no greater than about 1,000 nM,more preferably at an EC₅₀ of no greater than about 500 nM, morepreferably at an EC₅₀ of no greater than about 200 nM, even morepreferably at an EC₅₀ of no greater than about 100 nM, and mostpreferably at an EC₅₀ of no greater than about 10 nM. Also preferredcompounds are those of Formula I-VIb, and pharmaceutically acceptablesalts or solvates thereof, that are able to inhibit tubulin at an IC₅₀of no greater than about 2,000 nM, preferably no greater than about1,000 nM, more preferably less than about 500 nM, as determined by themethod and under conditions described in Example 145.

Exemplary compounds of the present invention are compounds provided inExamples 1-142; and pharmaceutically acceptable salts or prodrugsthereof, including but not limited to:

-   (2-Chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;    -   (2-Chloro-quinazolin-4-yl)-(4-methyl-phenyl)-methyl-amine;    -   (2-Chloro-quinazolin-4-yl)-(4-chloro-phenyl)-methyl-amine;    -   (2-Chloro-quinazolin-4-yl)-(4-nitro-phenyl)-methyl-amine;    -   (2-Chloro-quinazolin-4-yl)-(4-trifluoromethoxy-phenyl)-methyl-amine;-   N²-Hydroxyl-N⁴-(4-methoxy-phenyl)-N⁴-methyl-quinazoline-2,4-diamine;-   N²-(2-Hydroxylethyl)-N⁴-(4-methoxy-phenyl)-N⁴-methyl-quinazoline-2,4-diamine;-   N⁴-(4-methoxy-phenyl)-N⁴-methyl-quinazoline-2,4-diamine;    -   N²-(3,7-Dimethyl-octa-2,6-dienyl)-N⁴-(4-methoxy-phenyl)-N⁴-methyl-quinazoline-2,4-diamine;-   N⁴-(4-Methoxy-phenyl)-N⁴-methyl-N²-(2-morpholin-4-yl-ethyl)-quinazoline-2,4-diamine;-   (4-Methoxy-phenyl)-methyl-(2-morpholin-4-yl-quinazolin-4-yl)-amine;    -   N²-(3,7-Dimethyl-octa-2,6-dienyl)-N⁴-(4-methyl-phenyl)-N⁴-methyl-quinazoline-2,4-diamine;    -   (2-Chloro-6,7-dimethoxyquinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;    -   (5,6,7,8-Tetrahydro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;-   (2-Chloro-quinazolin-4-yl)-(4-methoxy-benzyl)-methyl-amine;-   (4-Methoxy-phenyl)-methyl-quinazolin-4-yl-amine;-   (4-Methyl-phenyl)-methyl-quinazolin-4-yl-amine;-   (2-Chloro-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl)-methyl-amine;-   (2-Chloro-quinazolin-4-yl)-isopropyl-(4-methoxy-phenyl)-amine;-   (2-Chloro-quinazolin-4-yl)-cyclohexyl-(4-methoxy-phenyl)-amine;-   (2-Chloro-quinazolin-4-yl)-(2,3-dimethoxy-phenyl)-methyl-amine;-   (2-Chloro-quinazolin-4-yl)-ethyl-(4-methoxy-phenyl)-amine;-   (2-Chloro-quinazolin-4-yl)-(2,4-dimethoxy-phenyl)-methyl-amine;-   (2-Chloro-quinazolin-4-yl)-(2,5-dimethoxy-phenyl)-methyl-amine;-   (2-Chloro-quinazolin-4-yl)-(3-methoxy-phenyl)-methyl-amine;-   (2-Chloro-quinazolin-4-yl)-(2-methoxy-phenyl)-methyl-amine;    -   N²-[2-(1H-Imidazol-4-yl)-ethyl]-N⁴-(4-methoxy-phenyl)-N⁴-methyl-quinazoline-2,4-diamine;    -   N²-(3-Dimethylamino-propyl)-N⁴-(4-methoxy-phenyl)-N⁴-methyl-quinazoline-2,4-diamine;    -   N²-(2-Hydroxyethyl)-N⁴-(6-methoxypyridin-3-yl)-N⁴-methyl-quinazoline-2,4-diamine;    -   N⁴-(6-methoxypyridin-3-yl)-N⁴-methyl-quinazoline-2,4-diamine;    -   (2-Chloro-quinazolin-4-yl)-(4-methylcarboxyphenyl)-methyl-amine;    -   (2-methoxy-quinazolin-4-yl)-(4-methoxyphenyl)-methylamine;    -   (2-Chloro-quinazolin-4-yl)-(4-hydroxyphenyl)-methylamine;    -   (2-Fluoromethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;-   (2-Chloro-6-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;    -   (2-Chloro-7-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;    -   (2-Chloro-5-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;    -   (2-Chloro-8-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;    -   (2,6-Dichloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;    -   (2,7-Dichloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;    -   (5-Chloro-2-isopropoxy-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;    -   (Isoquinolin-1-yl)-(4-methoxy-phenyl)-methyl-amine;    -   (4-Methoxy-phenyl)-methyl-(quinolin-4-yl)-amine;    -   (2-Chloro-quinazolin-4-yl)-(3,4-methylenedioxyphenyl)-methyl-amine;    -   (2-Chloro-quinazolin-4-yl)-(3,4-dimethoxy-phenyl)-methyl-amine;    -   (2-Chloro-quinazolin-4-yl)-(4-phenoxy-phenyl)-methyl-amine;    -   (2-Chloro-quinazolin-4-yl)-(4-propoxy-phenyl)-methyl-amine; and    -   (4-Methoxy-phenyl)-methyl-(2-methyl-quinazolin-4-yl)-amine;    -   (2-Chloro-quinazolin-4-yl)-(2,5-dimethoxy-phenyl)-amine;    -   5-Chloro-N²,N⁴-bis-(4-methoxy-phenyl)-N²,N⁴-dimethyl-quinazoline-2,4-diamine;    -   (2-Chloromethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;    -   (2-Ethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;    -   (2-Hydroxymethyl-quinazolin-4-yl)-4-methoxy-phenyl)-methyl-amine;    -   (2-Dimethylaminomethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;    -   (4-Methoxy-phenyl)-(2-phenyl-quinazolin-4-yl)-methyl-amine;    -   (4-Difluoromethoxy-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;    -   (3-Fluoro-4-methoxy-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;    -   (4-Isopropoxy-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;    -   (4-Ethyl-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;    -   (2-Methyl-quinazolin-4-yl)-(2,4,6-trimethoxy-phenyl)-methyl-amine;    -   (2,8-Dichloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;    -   (2,5-Dichloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;    -   (5-Methoxy-2-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;    -   (4-Methoxy-phenyl)-(2-methyl-pyrido[2,3-d]pyrimidin-4-yl)-methyl-amine;    -   (4-Hydroxy-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;    -   (2-Chloro-quinazolin-4-yl)-(4-ethoxy-phenyl)-methylamine;    -   (2-Methyl-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl)-methyl-amine;    -   (2-Fluoro-4-methoxy-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;    -   (2-Methyl-quinazolin-4-yl)-(4-nitro-phenyl)-methyl-amine;    -   (4-Amino-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;    -   (4-Azido-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;    -   (4-Amino-2,6-dibromo-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;    -   (4-Amino-2-bromo-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;    -   (4-Dimethylamino-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;    -   (4-Ethoxy-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;    -   (4-Methoxy-phenyl-2,3,5,6-d₄)-(2-methyl-quinazolin-4-yl)-methyl-amine;    -   (4-Methoxy-phenyl)-(2-methyl-6-nitro-quinazolin-4-yl)-methyl-amine;    -   (6-Amino-2-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;-   (6-Azido-2-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;-   (7-Amino-2-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;    -   (7-Azido-2-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;-   Ethyl    4-(N-(4-Methoxy-phenyl)-N-methylamino)quinazoline-2-carboxylate;    -   Succinimidyl        4-(N-Methyl-N-(2-methylquinazolin-4-yl)amino)benzoic Acid Ester;    -   (2-Methylthio-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;    -   (2-Azido-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;    -   (2-Dimethylamino-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;    -   (2-Methylamino-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;    -   (4-Fluoro-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;    -   (6-Methoxy-pyridazin-3-yl)-(2-methyl-quinazolin-4-yl)-methyl-amine;    -   (5-Methoxy-pyrazin-2-yl)-(2-methyl-quinazolin-4-yl)-methyl-amine;    -   (2-Dimethylamino-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl)-methyl-amine;    -   (2-Methylamino-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl)-methyl-amine;    -   (5-Methoxy-pyridin-2-yl)-(2-methyl-quinazolin-4-yl)-methyl-amine;    -   Difluoromethyl-(4-methoxy-phenyl)-(2-methyl-quinazolin-4-yl)-amine;    -   (4-Methoxy-phenyl)-(2-methyl-pteridin-4-yl)-methyl-amine;    -   (5-Methoxy-pyrimidin-2-yl)-(2-methyl-quinazolin-4-yl)-methyl-amine;    -   and pharmaceutically acceptable salts or prodrugs thereof.

In one embodiment, exemplary compounds of the invention include:

-   -   (2-Chloro-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl)-methyl-amine;    -   N²-(2-Hydroxyethyl)-N⁴-(6-methoxypyridin-3-yl)-N⁴-methyl-quinazoline-2,4-diamine;    -   N⁴-(6-Methoxypyridin-3-yl)-N⁴-methyl-quinazoline-2,4-diamine;    -   (2-Methyl-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl)-methyl-amine;    -   (6-Methoxy-pyridazin-3-yl)-(2-methyl-quinazolin-4-yl)-methyl-amine;    -   (5-Methoxy-pyrazin-2-yl)-(2-methyl-quinazolin-4-yl)-methyl-amine;    -   (2-Dimethylamino-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl)-methyl-amine;    -   (2-Methylamino-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl)-methyl-amine;    -   (2-Methyl-quinazolin-4-yl)-(pyrazin-2-yl)-methyl-amine;    -   (5-Methoxy-pyridin-2-yl)-(2-methyl-quinazolin-4-yl)-methyl-amine;        and    -   (5-Methoxy-pyrimidin-2-yl)-(2-methyl-quinazolin-4-yl)-methyl-amine;    -   or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, exemplary compounds of the invention include:

-   -   (4-Methoxy-phenyl)-(2-methyl-pyrido[2,3-d]pyrimidin-4-yl)-methyl-amine;        and    -   (4-Methoxy-phenyl)-(2-methyl-pteridin-4-yl)-methyl-amine;    -   or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, exemplary compounds of the invention include:

-   N²-Hydroxyl-N⁴-(4-methoxy-phenyl)-N⁴-methyl-quinazoline-2,4-diamine;-   N²-(2-Hydroxylethyl)-N⁴-(4-methoxy-phenyl)-N⁴-methyl-quinazoline-2,4-diamine;-   N⁴-(4-methoxy-phenyl)-N⁴-methyl-quinazoline-2,4-diamine;    -   N²-(3,7-Dimethyl-octa-2,6-dienyl)-N⁴-(4-methoxy-phenyl)-N⁴-methyl-quinazoline-2,4-diamine;-   N⁴-(4-Methoxy-phenyl)-N⁴-methyl-N²-(2-morpholin-4-yl-ethyl)-quinazoline-2,4-diamine;    -   (4-Methoxy-phenyl)-methyl-(2-morpholin-4-yl-quinazolin-4-yl)-amine;    -   N²-(3,7-Dimethyl-octa-2,6-dienyl)-N⁴-(4-methyl-phenyl)-N⁴-methyl-quinazoline-2,4-diamine;    -   N²-[2-(1H-Imidazol-4-yl)-ethyl]-N⁴-(4-methoxy-phenyl)-N⁴-methyl-quinazoline-2,4-diamine;    -   N²-(3-Dimethylamino-propyl)-N⁴-(4-methoxy-phenyl)-N⁴-methyl-quinazoline-2,4-diamine;    -   5-Chloro-N²,N⁴-bis-(4-methoxy-phenyl)-N²,N⁴-dimethyl-quinazoline-2,4-diamine;    -   6-Chloro-N²,N⁴-bis-(4-methoxy-phenyl)-N²,N⁴-dimethyl-quinazoline-2,4-diamine;    -   (2-Dimethylamino-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;        and    -   (2-Methylamino-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;    -   or a pharmaceutically acceptable salt or solvate thereof.

In yet another embodiment, exemplary compounds of the invention include:

-   -   (2-Fluoromethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;    -   (4-Methoxy-phenyl)-methyl-(2-methyl-quinazolin-4-yl)-amine;(2-Chloromethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;    -   (2-Ethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;    -   (4-carboxy-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;    -   Ethyl        4-(N-(4-methoxy-phenyl)-N-methylamino)quinazoline-2-carboxylate;    -   (2-hydroxymethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;    -   (2-Dimethylaminomethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;    -   (4-Difluoromethoxy-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;    -   (3-Fluoro-4-methoxy-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;    -   (4-Isopropoxy-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;    -   (4-Ethyl-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;    -   (5-Methoxy-2-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;    -   (4-Hydroxy-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;    -   (2-Fluoro-4-methoxy-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;    -   (2-Methyl-quinazolin-4-yl)-(4-nitro-phenyl)-methyl-amine;    -   (4-Amino-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;    -   (4-Azido-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;    -   (4-Amino-2,6-dibromo-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;    -   (4-Amino-2-bromo-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;    -   (4-Dimethylamino-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;    -   (4-Ethoxy-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;    -   (4-Methoxy-phenyl-2,3,5,6-d₄)-(2-methyl-quinazolin-4-yl)-methyl-amine;    -   (4-Methoxy-phenyl)-(2-methyl-6-nitro-quinazolin-4-yl)-methyl-amine;    -   (6-Amino-2-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;    -   (6-Azido-2-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;    -   (4-Methoxy-phenyl)-(2-methyl-7-nitro-quinazolin-4-yl)-methyl-amine;    -   (2,4,6-Trimethoxy-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;    -   (7-Amino-2-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;    -   (7-Azido-2-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;    -   (3,5-Dibromo-4-methoxyphenyl)-(2-methyl-6-nitro-quinazolin-4-yl)-methyl-amine;    -   (4-Fluoro-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine; and    -   Difluoromethyl-(4-methoxy-phenyl)-(2-methyl-quinazolin-4-yl)-amine;    -   or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, exemplary compounds of the invention include:

-   (2-Chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;    -   (2-Chloro-quinazolin-4-yl)-(4-methyl-phenyl)-methyl-amine;    -   (2-Chloro-quinazolin-4-yl)-(4-chloro-phenyl)-methyl-amine;    -   (2-Chloro-quinazolin-4-yl)-(4-nitro-phenyl)-methyl-amine;    -   (2-Chloro-quinazolin-4-yl)-(4-trifluoromethoxy-phenyl)-methyl-amine;    -   (2-Chloro-6,7-dimethoxyquinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;-   (2-Chloro-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl)-methyl-amine;-   (2-Chloro-quinazolin-4-yl)-isopropyl-(4-methoxy-phenyl)-amine;-   (2-Chloro-quinazolin-4-yl)-cyclohexyl-(4-methoxy-phenyl)-amine;-   (2-Chloro-quinazolin-4-yl)-(2,3-dimethoxy-phenyl)-methyl-amine;-   (2-Chloro-quinazolin-4-yl)-ethyl-(4-methoxy-phenyl)-amine;-   (2-Chloro-quinazolin-4-yl)-(2,4-dimethoxy-phenyl)-methyl-amine;-   (2-Chloro-quinazolin-4-yl)-(2,5-dimethoxy-phenyl)-methyl-amine;-   (2-Chloro-quinazolin-4-yl)-(3-methoxy-phenyl)-methyl-amine;-   (2-Chloro-quinazolin-4-yl)-(2-methoxy-phenyl)-methyl-amine;-   (2-Chloro-quinazolin-4-yl)-(4-methylcarboxyphenyl)-methyl-amine;-   (2-Chloro-quinazolin-4-yl)-(4-hydroxyphenyl)-methylamine;-   (2-Chloro-6-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;    -   (2-Chloro-7-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;    -   (2-Chloro-5-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;    -   (2-Chloro-8-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;    -   (2,6-Dichloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;    -   (2,7-Dichloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;-   (2-Chloro-quinazolin-4-yl)-(3,4-methylenedioxyphenyl)-methyl-amine;    -   (2-Chloro-quinazolin-4-yl)-(3,4-dimethoxy-phenyl)-methyl-amine;    -   (2-Chloro-quinazolin-4-yl)-(4-phenoxy-phenyl)-methyl-amine;-   (2-Chloro-quinazolin-4-yl)-(4-propoxy-phenyl)-methyl-amine;-   (2-Chloro-quinazolin-4-yl)-(4-ethoxy-phenyl)-methyl-amine;    -   (2,8-Dichloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;        and    -   (2,5-Dichloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;-   or a pharmaceutically acceptable salt or solvate thereof.

In yet another embodiment, exemplary compounds of the invention include:

-   (4-Methoxy-phenyl)-methyl-quinazolin-4-yl-amine; and-   (4-Methyl-phenyl)-methyl-quinazolin-4-yl-amine;    -   or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, exemplary compounds useful in the methods of theinvention include:

-   -   (2-methoxy-quinazolin-4-yl)-(4-methoxyphenyl)-methylamine; and

-   (5-Chloro-2-isopropoxy-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;

-   or a pharmaceutically acceptable salt or solvate thereof.

The term “alkyl” as employed herein by itself or as part of anothergroup refers to both straight and branched chain radicals of up to tencarbons. Useful alkyl groups include straight-chained and branched C₁₋₁₀alkyl groups, more preferably C₁₋₆ alkyl groups. Typical C₁₋₁₀ alkylgroups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl,tert-butyl, 3-pentyl, hexyl and octyl groups, which may be optionallysubstituted.

The term “alkenyl” as employed herein by itself or as part of anothergroup means a straight or branched chain radical of 2-10 carbon atoms,unless the chain length is limited thereto, including at least onedouble bond between two of the carbon atoms in the chain. Typicalalkenyl groups include ethenyl, 1-propenyl, 2-propenyl,2-methyl-1-propenyl, 1-butenyl and 2-butenyl.

The term “alkynyl” is used herein to mean a straight or branched chainradical of 2-10 carbon atoms, unless the chain length is limitedthereto, wherein there is at least one triple bond between two of thecarbon atoms in the chain. Typical alkynyl groups include ethynyl,1-propynyl, 1-methyl-2-propynyl, 2-propynyl, 1-butynyl and 2-butynyl.

Useful alkoxy groups include oxygen substituted by one of the C₁₋₁₀alkyl groups mentioned above, which may be optionally substituted.Alkoxy substituents include, without limitation, halo, morpholino, aminoincluding alkylamino and dialkylamino, and carboxy including estersthereof.

Useful alkylthio groups include sulfur substituted by one of the C₁₋₁₀alkyl groups mentioned above, which may be optionally substituted. Alsoincluded are the sulfoxides and sulfones of such alkylthio groups.

Useful amino groups include —NH₂, —NHR₁₈ and —NR₁₈R₁₉, wherein R₁₈ andR₁₈ are C₁₋₁₀ alkyl or cycloalkyl groups, or R₁₈ and R₁₉ are combinedwith the N to form a ring structure, such as a piperidine, or R₁₈ andR₁₉ are combined with the N and other group to form a ring, such as apiperazine. The alkyl group may be optionally substituted.

Optional substituents on the alkyl, alkenyl, alkynyl, cycloalkyl,carbocyclic and heterocyclic groups include one or more halo, hydroxy,carboxyl, amino, nitro, cyano, C₁-C₆ acylamino, C₁-C₆ acyloxy, C₁-C₆alkoxy, aryloxy, alkylthio, C₆-C₁₀ aryl, C₄-C₇ cycloalkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₆-C₁₀ aryl(C₂-C₆)alkenyl, C₆-C₁₀aryl(C₂-C₆)alkynyl, saturated and unsaturated heterocyclic orheteroaryl.

Optional substituents on the aryl, arylalkyl, arylalkenyl, arylalkynyland heteroaryl and heteroarylalkyl groups include one or more halo,C₁-C₆ haloalkyl, C₆-C₁₀ aryl, C₄-C₇ cycloalkyl, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₆-C₁₀ aryl(C₁-C₆)alkyl, C₆-C₁₀aryl(C₂-C₆)alkenyl, C₆-C_(1o) aryl(C₂-C₆)alkynyl, C₁-C₆ hydroxyalkyl,nitro, amino, ureido, cyano, C₁-C₆ acylamino, hydroxy, thiol, C₁-C₆acyloxy, azido, C₁-C₆ alkoxy, carboxy or C₁₋₂ alkylenedioxy (e.g.,methylenedioxy).

The term “aryl” as employed herein by itself or as part of another grouprefers to monocyclic, bicyclic or tricyclic aromatic groups containingfrom 6 to 14 carbons in the ring portion.

Useful aryl groups include C₆-₁₄ aryl, preferably C₆-₁₀ aryl. TypicalC₆₋₁₄ aryl groups include phenyl, naphthyl, phenanthrenyl, anthracenyl,indenyl, azulenyl, biphenyl, biphenylenyl and fluorenyl groups.

The term “carbocycle” as employed herein include cycloalkyl andpartially saturated carbocyclic groups. Useful cycloalkyl groups areC₃₋₈ cycloalkyl. Typical cycloalkyl groups include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

Useful saturated or partially saturated carbocyclic groups arecycloalkyl groups as described above, as well as cycloalkenyl groups,such as cyclopentenyl, cycloheptenyl and cyclooctenyl.

Useful halo or halogen groups include fluorine, chlorine, bromine andiodine.

The term “arylalkyl” is used herein to mean any of the above-mentionedC₁₋₁₀ alkyl groups substituted by any of the above-mentioned C₆₋₁₄ arylgroups. Preferably the arylalkyl group is benzyl, phenethyl ornaphthylmethyl.

The term “arylalkenyl” is used herein to mean any of the above-mentionedC₂₋₁₀ alkenyl groups substituted by any of the above-mentioned C₆₋₁₄aryl groups.

The term “arylalkynyl” is used herein to mean any of the above-mentionedC₂₋₁₀ alkynyl groups substituted by any of the above-mentioned C₆₋₁₄aryl groups.

The term “aryloxy” is used herein to mean oxygen substituted by one ofthe above-mentioned C₆₋₁₄ aryl groups, which may be optionallysubstituted. Useful aryloxy groups include phenoxy and 4-methylphenoxy.

The term “arylalkoxy” is used herein to mean any of the above mentionedC₁₋₁₀ alkoxy groups substituted by any of the above-mentioned arylgroups, which may be optionally substituted. Useful arylalkoxy groupsinclude benzyloxy and phenethyloxy.

Useful haloalkyl groups include C₁₋₁₀ alkyl groups substituted by one ormore fluorine, chlorine, bromine or iodine atoms, e.g., fluoromethyl,difluoromethyl, trifluoromethyl, pentafluoroethyl, 1,1-difluoroethyl,chloromethyl, chlorofluoromethyl and trichloromethyl groups.

Useful acylamino (acylamido) groups are any C₁₋₆ acyl (alkanoyl)attached to an amino nitrogen, e.g., acetamido, chloroacetamido,propionamido, butanoylamido, pentanoylamido and hexanoylamido, as wellas aryl-substituted C₁₋₆ acylamino groups, e.g., benzoylamido, andpentafluorobenzoylamido.

Useful acyloxy groups are any C₁₋₆ acyl (alkanoyl) attached to an oxy(—O—) group, e.g., formyloxy, acetoxy, propionoyloxy, butanoyloxy,pentanoyloxy and hexanoyloxy.

The term heterocycle is used herein to mean a saturated or partiallysaturated 3-7 membered monocyclic, or 7-10 membered bicyclic ringsystem, which consists of carbon atoms and from one to four heteroatomsindependently selected from the group consisting of O, N, and S, whereinthe nitrogen and sulfur heteroatoms can be optionally oxidized, thenitrogen can be optionally quaternized, and including any bicyclic groupin which any of the above-defined heterocyclic rings is fused to abenzene ring, and wherein the heterocyclic ring can be substituted oncarbon or on a nitrogen atom if the resulting compound is stable.

Useful saturated or partially saturated heterocyclic groups includetetrahydrofuranyl, pyranyl, piperidinyl, piperazinyl, pyrrolidinyl,imidazolidinyl, imidazolinyl, indolinyl, isoindolinyl, quinuclidinyl,morpholinyl, isochromanyl, chromanyl, pyrazolidinyl, pyrazolinyl,tetronoyl and tetramoyl groups.

The term “heteroaryl” as employed herein refers to groups having 5 to 14ring atoms; 6, 10 or 14π electrons shared in a cyclic array; andcontaining carbon atoms and 1, 2 or 3 oxygen, nitrogen or sulfurheteroactoms.

Useful heteroaryl groups include thienyl (thiophenyl), benzo[b]thienyl,naphtho[2,3-b]thienyl, thianthrenyl, furyl (furanyl), isobenzofuranyl,chromenyl, xanthenyl, phenoxanthiinyl, pyrrolyl, including withoutlimitation 2H-pyrrolyl, imidazolyl, pyrazolyl, pyridyl (pyridinyl),including without limitation 2-pyridyl, 3-pyridyl, and 4-pyridyl,pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl,3H-indolyl, indolyl, indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl,quinolyl, phthalzinyl, naphthyridinyl, quinozalinyl, cinnolinyl,pteridinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acrindinyl,perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl,isoxazolyl, furazanyl, phenoxazinyl, 1,4-dihydroquinoxaline-2,3-dione,7-aminoisocoumarin, pyrido[1,2-a]pyrimidin-4-one,pyrazolo[1,5-a]pyrimidinyl, including without limitationpyrazolo[1,5-a]pyrimidin-3-yl, 1,2-benzoisoxazol-3-yl, benzimidazolyl,2-oxindolyl and 2-oxobenzimidazolyl. Where the heteroaryl group containsa nitrogen atom in a ring, such nitrogen atom may be in the form of anN-oxide, e.g., a pyridyl N-oxide, pyrazinyl N-oxide and pyrimidinylN-oxide.

The term “heteroaryloxy” is used herein to mean oxygen substituted byone of the above-mentioned heteroaryl groups, which may be optionallysubstituted. Useful heteroaryloxy groups include pyridyloxy,pyrazinyloxy, pyrrolyloxy, pyrazolyloxy, imidazolyloxy andthiophenyloxy.

The term “heteroarylalkoxy” is used herein to mean any of theabove-mentioned C₁₋₁₀ alkoxy groups substituted by any of theabove-mentioned heteroaryl groups, which may be optionally substituted.

Some of the compounds of the present invention may exist asstereoisomers including optical isomers. The invention includes allstereoisomers and both the racemic mixtures of such stereoisomers aswell as the individual enantiomers that may be separated according tomethods that are well known to those of ordinary skill in the art.

Examples of pharmaceutically acceptable addition salts include inorganicand organic acid addition salts, such as hydrochloride, hydrobromide,phosphate, sulphate, citrate, lactate, tartrate, maleate, fumarate,mandelate and oxalate; and inorganic and organic base addition saltswith bases, such as sodium hydroxy, Tris(hydroxymethyl)aminomethane(TRIS, tromethane) and N-methyl-glucamine.

Examples of prodrugs of the compounds of the invention include thesimple esters of carboxylic acid containing compounds (e.g., thoseobtained by condensation with a C₁₋₄ alcohol according to methods knownin the art); esters of hydroxy containing compounds (e.g., thoseobtained by condensation with a C₁₋₄ carboxylic acid, C₃₋₆ dioic acid oranhydride thereof, such as succinic and fumaric anhydrides according tomethods known in the art); imines of amino containing compounds (e.g.,those obtained by condensation with a C₁₋₄ aldehyde or ketone accordingto methods known in the art); carbamate of amino containing compounds,such as those described by Leu, et. al., (J. Med. Chem. 42:3623-3628(1999)) and Greenwald, et. al., (J. Med. Chem. 42:3657-3667 (1999)); andacetals and ketals of alcohol containing compounds (e.g., those obtainedby condensation with chloromethyl methyl ether or chloromethyl ethylether according to methods known in the art).

The compounds of this invention may be prepared using methods known tothose skilled in the art, or the novel methods of this invention.Specifically, the compounds of this invention with Formulae I-VIb can beprepared as illustrated by the exemplary reaction in Scheme 1. Reactionof optionally substituted quinazoline-2,4-dione with phosphorylchlorideproduces the corresponding 2,4-dichloroquinazoline, which is reactedwith an optionally substituted aniline, such asN-methyl-4-methoxy-aniline, to produce the substituted2-chloro-4-anilino-quinazoline.

Compounds of this invention with Formulae I-VIb also could be preparedas illustrated by the exemplary reaction in Scheme 2. Reaction of thesubstituted 2-chloro-4-anilino-quinazoline with a nucleophile (R₂), suchas hydroxylamine, in isopropanol heated by microwave produces the2-nucleophile substituted -4-anilino-quinazoline, such as substitutedhydroxylamino. Other nucleophiles that can be used in the reactioninclude NaOMe, NaN₃, NaSMe, NH₃, NH₂Me, or NHMe₂, and the reaction canbe run at room temperature or elevated temperature.

Compounds of this invention with Formulae I-VIb, wherein Ar is asubstituted aryl or heteroaryl, could be prepared as illustrated by theexemplary reaction in Scheme 3. Reaction of 2,4-dichloroquinazoline witha substituted arylamine or heteroarylamine (Ar), such as a substitutedpyridin-3-ylamine, produces the corresponding 4-Ar-amino substituted2-chloro-quinazoline, which is alkylated with a haloalkyl, such asmethylated by reaction with methyl iodide in the presence of a base suchas NaH, to produce the corresponding 4-N-methyl-Ar-amino substituted2-chloro-quinazoline.

Alternatively, compounds of this invention with Formulae I-VIb alsocould be prepared as illustrated by the exemplary reaction in Scheme 4.The N-alkyl-arylamine or N-alkyl-heteroarylamine could be prepared byreaction of the arylamine or heteroarylamine with a ketone or aldehyde,such as acetone, in the presence of a reducing agent, such as NaCNBH₃.The N-alkyl-arylamine or N-alkyl-heteroarylamine is then reacted withoptionally substituted 2,4-dichloroquinazoline to produce thecorresponding 4-substituted 2-chloro-quinazoline.

Compounds of this invention with Formulae I-VIb also could be preparedas illustrated by the exemplary reaction in Scheme 5. Reaction ofoptionally substituted 2-amino-benzoic acid, such as2-amino-5-methyl-benzoic acid, with potassium cyanate in the presence ofan acid, such as acetic acid, produces the corresponding optionallysubstituted quinazoline-2,4-dione, such as6-methyl-quinazoline-2,4-dione, which is converted to the correspondingoptionally substituted 2,4-dichloroquinazoline, such as6-methyl-2,4-dichloroquinazoline by reaction with phosphorylchloride.Reaction of optionally substituted 2,4-dichloroquinazoline, such as6-methyl-2,4-dichloroquinazoline with a substituted arylamine orheteroarylamine, such as N-methyl-4-methoxy-aniline, produces thecorresponding 4-substituted 2-chloro-quinazoline, such as substituted2-chloro-4-anilino-quinazoline.

Compounds of this invention with Formulae I-VIb, wherein R₂ is anoptionally substituted alkyl group, could be prepared as illustrated bythe exemplary reaction in Scheme 6. Reaction of 2-amino-benzoic acidmethyl ester with an optionally substituted acetonitrile, such asfluoro-acetonitrile, in the presence of HCl produces the corresponding2-substituted quinazoline-4(3H)-one, such as2-fluoromethyl-quinazoline-4(3H)-one, which is converted to2-substituted 4-chloro-quinazoline, such as4-chloro-2-fluoromethyl-quinazoline by reaction with phosphorylchloride.Reaction of 2-substituted 4-chloro-quinazoline, such as4-chloro-2-fluoromethyl-quinazoline with a substituted aniline, such asN-methyl-4-methoxy-aniline, produces the corresponding 2-substituted4-anilino-quinazoline, such as 2-fluoromethyl-4-anilino-quinazoline.Other substituted acetonitriles that can be used for the reactioninclude chloro-acetonitrile and bromo-acetonitrile, as well asacetonitrile and propionitrile.

Compounds of this invention with Formulae I-VIb, wherein R₂ is asubstituted alkyl group, could also be prepared as illustrated by theexemplary reaction in Scheme 7. Reaction of a substituted2-chloroalkyl-4-(N-alkyl-arylamine orN-alkyl-heteroarylamine)-quinazoline, such asN-methyl-2-chloromethyl-4-anilino-quinazoline, with a nucleophile, suchas NHMe₂, produces the substituted2-dimethylaminomethyl-4-anilino-quinazoline. Other nucleophiles that canbe used in the reaction include NaOMe, NaN₃, NaSMe, NH₃, NH₂Me, orNHMe₂, and the reaction can be run at room temperature and elevatedtemperature.

Compounds of this invention with Formulae I-VIb, wherein R₁ is asubstituted alkyl, could be prepared as illustrated by the exemplaryreaction in Scheme 8. For example, reaction of an optionally substituted4-(arylamine or heteroarylamine)-quinazoline, such as2-methyl-4-(6-methoxy-pyridin-3-ylamino)-quinazoline, with a substitutedhaloalkyl, such as difluoromethyl chloride, in the presence of a basesuch as NaH, produces the corresponding 4-(N-alkyl-arylamine orN-alkyl-heteroarylamine)-quinazoline, such as2-methyl-N⁴-difluoromethyl-4-(4-methoxy-pyridin-3-ylamino)-quinazoline.

Compounds of this invention with Formula I-VIb, wherein R₂ is an alkylgroup, could be prepared as illustrated by the exemplary reaction inScheme 9. Reaction of a substituted 2-amino-benzoic acid, such as2-amino-5-nitro-benzoic acid, with acetic anhydride, produces thecorresponding substituted 2-methyl-4H-benzo[d][1,3]oxazine-4-one, suchas 2-methyl-6-nitro-4H-benzo[d][1,3]oxazine-4-one, which is converted tothe corresponding quinazoline-4(3H)-one, such as2-methyl-6-nitro-quinazoline-4(3H)-one, by treatment with ammonia indioxane. The compound is then converted to the corresponding 4-chloro-quinazoline, such as 4-chloro-2-methyl-6-nitro-quinazoline by reactionwith phosphorylchloride. Reaction of the 4-chloro-quinazoline, such as4-chloro-2-methyl-6-nitro-quinazoline with a substituted arylamine orheteroarylamine, such as N-methyl-4-methoxy-aniline, produces thecorresponding 4-(arylamino or heteroarylamino)-quinazoline, such assubstituted 2-methyl-6-nitro-4-anilino-quinazoline. Other substituted2-amino-benzoic acid that can be used for the reaction include2-amino-4-nitro-benzoic acid, 2-amino-5-chloro-benzoic acid.

Compounds substituted with a nitro group can be reduced by hydrogenationunder H₂ with Pd to produce the amino compound, which can be convertedto the azido compounds by diazotization followed by treatment with NaN₃.

Compounds of this invention with Formula I-VIb, wherein ring A is acarbocycle, could be prepared as illustrated by the exemplary reactionin Scheme 10. Reaction of optionally substituted5,6,7,8-tetrahydro-quinazoline-4(3H)-one with phosphorylchlorideproduces the corresponding optionally substituted5,6,7,8-tetrahydro-4-chloroquinazoline, which is reacted with anoptionally substituted N-alkyl-arylamine or N-alkyl-heteroarylamine,such as N-methyl-4-methoxy-aniline, to produce the correspondingoptionally substituted 5,6,7,8-tetrahydro-4-(N-alkyl-arylamine orN-alkyl-heteroarylamine)-quinazoline.

Compounds of this invention with Formular I-VIb, wherein ring A is aheteroaryl or heterocycle, such as pyrido, could be prepared asillustrated by the exemplary reaction in Scheme 11. Reaction of anamino-nicotinic acid, such as 2-amino-nicotinic acid, with acetylchloride, in the presence of base, such as triethylamine, produces thecorresponding amide, which is treated with ammonium acetate to producethe corresponding 2-methyl-pyrido[2,3-d](heteroaryl orheterocycle)-4-ol, such as 2-methyl-pyrido[2,3-d]pyrimidin-4-ol. Theresulting compound is then converted to the corresponding4-chloro-2-methyl-pyrido[2,3-d](heteroaryl or heterocycle), such as4-chloro-2-methyl-pyrido[2,3-d]pyrimidine by reaction withphosphorylchloride, which is treated with an optionally substitutedarylamino or heteroarylamino, such as N-methyl-4-methoxy-aniline toproduce the corresponding optionally substituted 4-(arylamino orheteroarylamino)-2-methyl-pyrido[2,3-d](heteroaryl or heterocycle), suchas substituted 4-anilino-2-methyl-pyrido[2,3-d]pyrimidine.

Additional exemplary compounds may be synthesized according to thesynthesis schemes below:

An important aspect of the present invention is the discovery thatcompounds having Formulae I-VIb are activators of caspases and inducersof apoptosis. Another important aspect of the invention is the discoverythat compounds having Formulae I-Vc are inhibitors of tubulinpolymerization. Therefore, these compounds are useful in treatingdiseases that are responsive to activating caspases, inducing apoptosis,or inhibiting tubulin. For example, these compounds are useful in avariety of clinical conditions in which there is uncontrolled cellgrowth and spread of abnormal cells, such as in the case of cancer.

The present invention also includes a therapeutic method comprisingadministering to an animal an effective amount of a compound, or apharmaceutically acceptable salt or prodrug of said compound of FormulaeI-Vc, wherein said therapeutic method is useful to treat cancer, whichis a group of diseases characterized by the uncontrolled growth andspread of abnormal cells. Such diseases include, but are not limited to,Hodgkin's disease, non-Hodgkin's lymphoma, acute lymphocytic leukemia,chronic lymphocytic leukemia, multiple myeloma, neuroblastoma, breastcarcinoma, ovarian carcinoma, lung carcinoma, Wilms' tumor, cervicalcarcinoma, testicular carcinoma, soft-tissue sarcoma, primarymacroglobulinemia, bladder carcinoma, chronic granulocytic leukemia,primary brain carcinoma, malignant melanoma, small-cell lung carcinoma,stomach carcinoma, colon carcinoma, malignant pancreatic insulinoma,malignant carcinoid carcinoma, choriocarcinoma, mycosis fungoides, heador neck carcinoma, osteogenic sarcoma, pancreatic carcinoma, acutegranulocytic leukemia, hairy cell leukemia, neuroblastoma,rhabdomyosarcoma, Kaposi's sarcoma, genitourinary carcinoma, thyroidcarcinoma, esophageal carcinoma, malignant hypercalcemia, cervicalhyperplasia, renal cell carcinoma, endometrial carcinoma, polycythemiavera, essential thrombocytosis, adrenal cortex carcinoma, skin cancer,and prostatic carcinoma.

In practicing the therapeutic methods, effective amounts of compositionscontaining therapeutically effective concentrations of the compoundsformulated for oral, intravenous, local and topical application, for thetreatment of neoplastic diseases and other diseases, are administered toan individual exhibiting the symptoms of one or more of these disorders.The amounts are effective to ameliorate or eliminate one or moresymptoms of the disorders. An effective amount of a compound fortreating a particular disease is an amount that is sufficient toameliorate, or in some manner reduce, the symptoms associated with thedisease. Such amount may be administered as a single dosage or may beadministered according to a regimen, whereby it is effective. The amountmay cure the disease but, typically, is administered in order toameliorate the symptoms of the disease. Typically, repeatedadministration is required to achieve the desired amelioration ofsymptoms.

Another aspect of the present invention is to provide a pharmaceuticalcomposition, containing an effective amount of a compound of FormulaeI-VIb, or a pharmaceutically acceptable salt of said compound, inadmixture with one or more pharmaceutically acceptable carriers ordiluents.

In one embodiment, a pharmaceutical composition comprising a compound ofFormulae I-Vc disclosed herein, or a pharmaceutically acceptable salt ofsaid compound, in combination with a pharmaceutically acceptable vehicleis provided.

Preferred pharmaceutical compositions comprise compounds of FormulaeI-VIb, and pharmaceutically acceptable salts, esters, or prodrugsthereof, that are able to induce caspase activation as determined by themethod described in Example145, preferably at an EC₅₀ no greater than1,000 nM, more preferably at an EC₅₀ no greater than 500 nM, morepreferably at an EC₅₀ no greater than 200 nM, more preferably at an EC₅₀no greater than 100, and most preferably at an EC₅₀ no greater than 10nM. Other preferred compositions comprise compounds of Formula I-VIb,and pharmaceutically acceptable salts, esters, or prodrugs thereof, thatare able to inhibit tubulin polymerization as determined by the methoddescribed in Example147.

Another embodiment of the present invention is directed to a compositioneffective to inhibit neoplasia comprising a compound, or apharmaceutically acceptable salt or prodrug of said compound of FormulaeI-VIb, which functions as a caspase cascade activator and inducer ofapoptosis or inhibitor of tubulin polymerization, in combination with atleast one known cancer chemotherapeutic agent, or a pharmaceuticallyacceptable salt of said agent. Examples of known cancer chemotherapeuticagents which may be used for combination therapy include, but not arelimited to alkylating agents, such as busulfan, cis-platin, mitomycin C,and carboplatin; antimitotic agents, such as colchicine, vinblastine,paclitaxel, and docetaxel; topo I inhibitors, such as camptothecin andtopotecan; topo II inhibitors, such as doxorubicin and etoposide;RNA/DNA antimetabolites, such as 5-azacytidine, 5-fluorouracil andmethotrexate; DNA antimetabolites, such as 5-fluoro-2′-deoxy-uridine,ara-C, hydroxyurea and thioguanine; EGFR inhibitors, such as Iressa®(gefitinib) and Tarceva® (erlotinib); proteosome inhibitors; antibodies,such as campath, Herceptin® (trastuzumab), Avastin® (bevacizumab), orRituxan® (rituximab). Other known cancer chemotherapeutic agents whichmay be used for combination therapy include melphalan, chlorambucil,cyclophosamide, ifosfamide, vincristine, mitoguazone, epirubicin,aclarubicin, bleomycin, mitoxantrone, elliptinium, fludarabine,octreotide, retinoic acid, tamoxifen, Gleevec® (imatinib mesylate) andalanosine.

In practicing the methods of the present invention, the compound of theinvention may be administered together with at least one knownchemotherapeutic agent as part of a unitary pharmaceutical composition.Alternatively, the compound of the invention may be administered apartfrom at least one known cancer chemotherapeutic agent. In oneembodiment, the compound of the invention and at least one known cancerchemotherapeutic agent are administered substantially simultaneously,i.e. the compounds are administered at the same time or one after theother, so long as the compounds reach therapeutic levels in the blood atthe same time. On another embodiment, the compound of the invention andat least one known cancer chemotherapeutic agent are administeredaccording to their individual dose schedule, so long as the compoundsreach therapeutic levels in the blood.

It has been reported that alpha-1-adrenoceptor antagonists, such asdoxazosin, terazosin, and tamsulosin can inhibit the growth of prostatecancer cell via induction of apoptosis (Kyprianou, N., et al., CancerRes 60:4550-4555, (2000)). Therefore, another embodiment of the presentinvention is directed to a composition effective to inhibit neoplasiacomprising a compound, or a pharmaceutically acceptable salt or prodrugof a compound described herein, which functions as a caspase cascadeactivator and inducer of apoptosis or inhibitor of tubulinpolymerization, in combination with at least one knownalpha-1-adrenoceptor antagonists, or a pharmaceutically acceptable saltof said agent. Examples of known alpha-1-adrenoceptor antagonists, whichcan be used for combination therapy include, but are not limited to,doxazosin, terazosin, and tamsulosin.

It has been reported that sigma-2 receptors are expressed in highdensities in a variety of tumor cell types (Vilner, B. J., et al.,Cancer Res. 55: 408-413 (1995)) and that sigma-2 receptor agonists, suchas CB-64D, CB-184 and haloperidol activate a novel apoptotic pathway andpotentiate antineoplastic drugs in breast tumor cell lines. (Kyprianou,N., et al., Cancer Res. 62:313-322 (2002)). Therefore, anotherembodiment of the present invention is directed to a compositioneffective to inhibit neoplasia comprising a compound, or apharmaceutically acceptable salt or prodrug of a compound describedherein, which functions as a caspase cascade activator and inducer ofapoptosis or inhibitor of tubulin polymerization, in combination with atleast one known sigma-2 receptor agonist, or a pharmaceuticallyacceptable salt of said agonist. Examples of known sigma-2 receptoragonists which can be used for combination therapy include, but are notlimited to, CB-64D, CB-184 and haloperidol.

It has been reported that combination therapy with lovastatin, a HMG-CoAreductase inhibitor, and butyrate, an inducer of apoptosis in the Lewislung carcinoma model in mice, showed potentiating antitumor effects(Giermasz, A., et al., Int. J. Cancer 97:746-750 (2002)). Therefore,another embodiment of the present invention is directed to a compositioneffective to inhibit neoplasia comprising a compound, or apharmaceutically acceptable salt or prodrug of a compound describedherein, which functions as a caspase cascade activator and inducer ofapoptosis or inhibitor of tubulin polymerization, in combination with atleast one known HMG-CoA reductase inhibitor, or a pharmaceuticallyacceptable salt of said agent. Examples of known HMG-CoA reductaseinhibitors, which can be used for combination therapy include, but arenot limited to, lovastatin, simvastatin, pravastatin, fluvastatin,atorvastatin and cerivastatin.

It has been reported that HIV protease inhibitors, such as indinavir orsaquinavir, have potent anti-angiogenic activities and promoteregression of Kaposi sarcoma (Sgadari, C., et al., Nat. Med. 8:225-232(2002)). Therefore, another embodiment of the present invention isdirected to a composition effective to inhibit neoplasia comprising acompound, or a pharmaceutically acceptable salt or prodrug of a compounddescribed herein, which functions as a caspase cascade activator andinducer of apoptosis or inhibitor of tubulin polymerization, incombination with at least one known HIV protease inhibitor, or apharmaceutically acceptable salt of said agent. Examples of known HIVprotease inhibitors, which can be used for combination therapy include,but are not limited to, amprenavir, abacavir, CGP-73547, CGP-61755,DMP-450, indinavir, nelfinavir, tipranavir, ritonavir, saquinavir,ABT-378, AG 1776, and BMS-232,632.

It has been reported that synthetic retinoids, such as fenretinide(N-(4-hydroxyphenyl)retinamide, 4HPR), have good activity in combinationwith other chemotherapeutic agents, such as cisplatin, etoposide orpaclitaxel in small-cell lung cancer cell lines (Kalemkerian, G. P., etal., Cancer Chemother. Pharmacol. 43:145-150 (1999)). 4HPR also wasreported to have good activity in combination with gamma-radiation onbladder cancer cell lines (Zou, C., et al., Int. J. Oncol. 13:1037-1041(1998)). Therefore, another embodiment of the present invention isdirected to a composition effective to inhibit neoplasia comprising acompound, or a pharmaceutically acceptable salt or prodrug of a compounddescribed herein, which functions as a caspase cascade activator andinducer of apoptosis or inhibitor of tubulin polymerization, incombination with at least one known retinoid and synthetic retinoid, ora pharmaceutically acceptable salt of said agent. Examples of knownretinoids and synthetic retinoids, which can be used for combinationtherapy include, but are not limited to, bexarotene, tretinoin,13-cis-retinoic acid, 9-cis-retinoic acid, α-difluoromethylornithine,ILX23-7553, fenretinide, and N-4-carboxyphenyl retinamide.

It has been reported that proteasome inhibitors, such as lactacystin,exert anti-tumor activity in vivo and in tumor cells in vitro, includingthose resistant to conventional chemotherapeutic agents. By inhibitingNF-kappaB transcriptional activity, proteasome inhibitors may alsoprevent angiogenesis and metastasis in vivo and further increase thesensitivity of cancer cells to apoptosis (Almond, J. B., et al.,Leukemia 16:433-443 (2002)). Therefore, another embodiment of thepresent invention is directed to a composition effective to inhibitneoplasia comprising a compound, or a pharmaceutically acceptable saltor prodrug of a compound described herein, which functions as a caspasecascade activator and inducer of apoptosis or inhibitor of tubulinpolymerization, in combination with at least one known proteasomeinhibitor, or a pharmaceutically acceptable salt of said agent. Examplesof known proteasome inhibitors, which can be used for combinationtherapy include, but are not limited to, lactacystin, MG-132, andPS-341.

It has been reported that tyrosine kinase inhibitors, such as STI571(Gleevec® (imatinib mesylate)), have potent synergetic effect incombination with other anti-leukemic agents, such as etoposide (Liu, W.M., et al. Br. J. Cancer 86:1472-1478 (2002)). Therefore, anotherembodiment of the present invention is directed to a compositioneffective to inhibit neoplasia comprising a compound, or apharmaceutically acceptable salt or prodrug of a compound describedherein, which functions as a caspase cascade activator and inducer ofapoptosis or inhibitor of tubulin polymerization, in combination with atleast one known tyrosine kinase inhibitor, or a pharmaceuticallyacceptable salt of said agent. Examples of known tyrosine kinaseinhibitors, which can be used for combination therapy include, but arenot limited to, Gleevec® (imatinib mesylate), ZD1839 Iressa®(gefitinib), SH268, genistein, CEP2563, SU6668, SU11248, and EMD121974.

It has been reported that prenyl-protein transferase inhibitors, such asfarnesyl protein transferase inhibitor R115777, possess preclinicalantitumor activity against human breast cancer (Kelland, L. R., et. al.,Clin. Cancer Res. 7:3544-3550 (2001)). Synergy of the proteinfarnesyltransferase inhibitor SCH66336 and cisplatin in human cancercell lines also has been reported (Adjei, A. A., et al., Clin. Cancer.Res. 7:1438-1445 (2001)). Therefore, another embodiment of the presentinvention is directed to a composition effective to inhibit neoplasiacomprising a compound, or a pharmaceutically acceptable salt or prodrugof a compound described herein, which functions as a caspase cascadeactivator and inducer of apoptosis, in combination with at least oneknown prenyl-protein transferase inhibitor, including farnesyl proteintransferase inhibitor, inhibitors of geranylgeranyl-protein transferasetype I (GGPTase-I) and geranylgeranyl-protein transferase type-II, or apharmaceutically acceptable salt of said agent. Examples of knownprenyl-protein transferase inhibitors, which can be used for combinationtherapy include, but are not limited to, R115777, 5CH66336, L-778,123,BAL9611 and TAN-1813.

It has been reported that cyclin-dependent kinase (CDK) inhibitors, suchas flavopiridol, have potent synergetic effect in combination with otheranticancer agents, such as CPT-11, a DNA topoisomerase I inhibitor inhuman colon cancer cells (Motwani, M., et al., Clin. Cancer Res.7:4209-4219, (2001)). Therefore, another embodiment of the presentinvention is directed to a composition effective to inhibit neoplasiacomprising a compound, or a pharmaceutically acceptable salt or prodrugof a compound described herein, which functions as a caspase cascadeactivator and inducer of apoptosis or inhibitor of tubulinpolymerization, in combination with at least one known cyclin-dependentkinase inhibitor, or a pharmaceutically acceptable salt of said agent.Examples of known cyclin-dependent kinase inhibitor, which can be usedfor combination therapy include, but are not limited to, flavopiridol,UCN-01, roscovitine and olomoucine.

It has been reported that in preclinical studies COX-2 inhibitors werefound to block angiogenesis, suppress solid tumor metastases, and slowthe growth of implanted gastrointestinal cancer cells (Blanke, C. D.,Oncology (Huntingt) 16(No. 4 Suppl. 3):17-21 (2002)). Therefore, anotherembodiment of the present invention is directed to a compositioneffective to inhibit neoplasia comprising a compound, or apharmaceutically acceptable salt or prodrug of a compound describedherein, which functions as a caspase cascade activator and inducer ofapoptosis or inhibitor of tubulin polymerization, in combination with atleast one known COX-2 inhibitor, or a pharmaceutically acceptable saltof said inhibitor. Examples of known COX-2 inhibitors which can be usedfor combination therapy include, but are not limited to, celecoxib,valecoxib, and rofecoxib.

Another embodiment of the present invention is directed to a compositioneffective to inhibit neoplasia comprising a bioconjugate of a compounddescribed herein, which functions as a caspase cascade activator andinducer of apoptosis or inhibitor of tubulin polymerization, inbioconjugation with at least one known therapeutically useful antibody,such as Herceptin® (trastuzumab) or Rituxan® (rituximab), growthfactors, such as DGF, NGF; cytokines, such as IL-2, IL-4, or anymolecule that binds to the cell surface. The antibodies and othermolecules will deliver a compound described herein to its targets andmake it an effective anticancer agent. The bioconjugates could alsoenhance the anticancer effect of therapeutically useful antibodies, suchas Herceptin® (trastuzumab) or Rituxan® (rituximab).

Similarly, another embodiment of the present invention is directed to acomposition effective to inhibit neoplasia comprising a compound, or apharmaceutically acceptable salt or prodrug of a compound describedherein, which functions as a caspase cascade activator and inducer ofapoptosis or inhibitor of tubulin polymerization, in combination withradiation therapy. In this embodiment, the compound of the invention maybe administered at the same time as the radiation therapy isadministered or at a different time.

Yet another embodiment of the present invention is directed to acomposition effective for post-surgical treatment of cancer, comprisinga compound, or a pharmaceutically acceptable salt or prodrug of acompound described herein, which functions as a caspase cascadeactivator and inducer of apoptosis or inhibitor of tubulinpolymerization. The invention also relates to a method of treatingcancer by surgically removing the cancer and then treating the animalwith one of the pharmaceutical compositions described herein.

A wide range of immune mechanisms operate rapidly following exposure toan infectious agent. Depending on the type of infection, rapid clonalexpansion of the T and B lymphocytes occurs to combat the infection. Theelimination of the effector cells following an infection is one of themajor mechanisms for maintaining immune homeostasis. The elimination ofthe effector cells has been shown to be regulated by apoptosis.Autoimmune diseases have lately been determined to occur as aconsequence of deregulated cell death. In certain autoimmune diseases,the immune system directs its powerful cytotoxic effector mechanismsagainst specialized cells, such as oligodendrocytes in multiplesclerosis, the beta cells of the pancreas in diabetes mellitus, andthyrocytes in Hashimoto's thyroiditis (Ohsako, S. & Elkon, K. B., CellDeath Differ. 6:13-21(1999)). Mutations of the gene encoding thelymphocyte apoptosis receptor Fas/APO-1/CD95 are reported to beassociated with defective lymphocyte apoptosis and autoimmunelymphoproliferative syndrome (ALPS), which is characterized by chronic,histologically benign splenomegaly, generalized lymphadenopathy,hypergammaglobulinemia, and autoantibody formation. (Infante, A. J., etal., J. Pediatr. 133:629-633 (1998) and Vaishnaw, A. K., et al., J.Clin. Invest. 103:355-363 (1999)). It was reported that overexpressionof Bcl-2, which is a member of the bcl-2 gene family of programmed celldeath regulators with anti-apoptotic activity, in developing B cells oftransgenic mice, in the presence of T cell dependent costimulatorysignals, results in the generation of a modified B cell repertoire andin the production of pathogenic autoantibodies (Lopez-Hoyos, M., et al.,Int. J. Mol. Med. 1:475-483 (1998)). It is therefore evident that manytypes of autoimmune disease are caused by defects of the apoptoticprocess. One treatment strategy for such diseases is to turn onapoptosis in the lymphocytes that are causing the autoimmune disease(O'Reilly, L. A. & Strasser, A., Inflamm. Res. 48:5-21 (1999)).

Fas-Fas ligand (FasL) interaction is known to be required for themaintenance of immune homeostasis. Experimental autoimmune thyroiditis(EAT), characterized by autoreactive T and B cell responses and a markedlymphocytic infiltration of the thyroid, is a good model to study thetherapeutic effects of FasL. Batteux, F., et al., (J. Immunol.162:603-608 (1999)) reported that by direct injection of DNA expressionvectors encoding FasL into the inflamed thyroid, the development oflymphocytic infiltration of the thyroid was inhibited and induction ofinfiltrating T cells death was observed. These results show that FasLexpression on thyrocytes may have a curative effect on ongoing EAT byinducing death of pathogenic autoreactive infiltrating T lymphocytes.

Bisindolylmaleimide VIII is known to potentiate Fas-mediated apoptosisin human astrocytoma 1321N1 cells and in Molt-4T cells; both of whichwere resistant to apoptosis induced by anti-Fas antibody in the absenceof bisindolylmaleimide VIII. Potentiation of Fas-mediated apoptosis bybisindolylmaleimide VIII was reported to be selective for activated,rather than non-activated, T cells, and was Fas-dependent. Zhou T., etal., (Nat. Med. 5:42-48 (1999)) reported that administration ofbisindolylmaleimide VIII to rats during autoantigen stimulationprevented the development of symptoms of T cell-mediated autoimmunediseases in two models, the Lewis rat model of experimental allergicencephalitis and the Lewis adjuvant arthritis model. Therefore, theapplication of a Fas-dependent apoptosis enhancer, such asbisindolylmaleimide VIII, may be therapeutically useful for the moreeffective elimination of detrimental cells and inhibition of Tcell-mediated autoimmune diseases. Therefore, an effective amount of acompound, or a pharmaceutically acceptable salt or prodrug of thecompound of Formulae I-Vc, which functions as a caspase cascadeactivator and inducer of apoptosis, is an effective treatment forautoimmune diseases.

Psoriasis is a chronic skin disease that is characterized by scaly redpatches. Psoralen plus ultraviolet A (PUVA) is a widely used andeffective treatment for psoriasis vulgaris. Coven, et al.,Photodermatol. Photoimmunol. Photomed. 15:22-27 (1999), reported thatlymphocytes treated with psoralen 8-MOP or TMP and UVA, displayed DNAdegradation patterns typical of apoptotic cell death. Ozawa, et al., J.Exp. Med. 189:711-718 (1999) reported that induction of T cell apoptosiscould be the main mechanism by which 312-nm UVB resolves psoriasis skinlesions. Low doses of methotrexate may be used to treat psoriasis torestore a clinically normal skin. Heenen, et al., Arch. Dermatol. Res.290:240-245 (1998), reported that low doses of methotrexate may induceapoptosis and that this mode of action could explain the reduction inepidermal hyperplasia during treatment of psoriasis with methotrexate.Therefore, an effective amount of a compound, or a pharmaceuticallyacceptable salt or prodrug of the compound of Formulae I-Vc, whichfunctions as a caspase cascade activator and inducer of apoptosis, is aneffective treatment for hyperproliferative skin diseases, such aspsoriasis.

Synovial cell hyperplasia is a characteristic of patients withrheumatoid arthritis (RA). It is believed that excessive proliferationof RA synovial cells, as well as defects in synovial cell death, may beresponsible for synovial cell hyperplasia. Wakisaka, et al., Clin. Exp.Immunol. 114:119-128 (1998), found that although RA synovial cells coulddie via apoptosis through a Fas/FasL pathway, apoptosis of synovialcells was inhibited by proinflammatory cytokines present within thesynovium. Wakisaka, et al. also suggested that inhibition of apoptosisby the proinflammatory cytokines may contribute to the outgrowth ofsynovial cells, and lead to pannus formation and the destruction ofjoints in patients with RA. Therefore, an effective amount of acompound, or a pharmaceutically acceptable salt or prodrug of thecompound of Formulae I-Vc, which functions as a caspase cascadeactivator and inducer of apoptosis, is an effective treatment forrheumatoid arthritis.

There has been an accumulation of convincing evidence that apoptosisplays a major role in promoting resolution of the acute inflammatoryresponse. Neutrophils are constitutively programmed to undergoapoptosis, thus limiting their pro-inflammatory potential and leading torapid, specific, and non-phlogistic recognition by macrophages andsemi-professional phagocytes (Savill, J., J. Leukoc. Biol. 61:375-380(1997)). Boirivant, et al., Gastroenterology 116:557-565 (1999),reported that lamina propria T cells, isolated from areas ofinflammation in Crohn's disease, ulcerative colitis, and otherinflammatory states, manifest decreased CD2 pathway-induced apoptosis.In addition, studies of cells from inflamed Crohn's disease tissueindicate that this defect is accompanied by elevated Bcl-2 levels.Therefore, an effective amount of a compound, or a pharmaceuticallyacceptable salt or prodrug of the compound of Formulae I-Vc, whichfunctions as a caspase cascade activator and inducer of apoptosis, is aneffective treatment for inflammation.

Caspase cascade activators and inducers of apoptosis may also be adesirable therapy in the elimination of pathogens, such as HIV,Hepatitis C and other viral pathogens. The long lasting quiecence,followed by disease progression, may be explained by an anti-apoptoticmechanism of these pathogens leading to persistent cellular reservoirsof the virions. It has been reported that HIV-linfected T leukemia cellsor peripheral blood mononuclear cells (PBMCs) underwent enhanced viralreplication in the presence of the caspase inhibitor Z-VAD-fmk.Furthermore, Z-VAD-fmk also stimulated endogenous virus production inactivated PBMCs derived from HIV-1-infected asymptomatic individuals(Chinnaiyan, A., et al., Nat. Med. 3:333 (1997)). Therefore, apoptosisserves as a beneficial host mechanism to limit the spread of HIV and newtherapeutics using caspase/apoptosis activators are useful to clearviral reservoirs from the infected individuals. Similarly, HCV infectionalso triggers anti-apoptotic mechanisms to evade the host's immunesurveillance leading to viral persistence and hepatocarcinogenesis (Tai,D. I., et al. Hepatology 3:656-64 (2000)). Therefore, apoptosis inducersare useful as therapeutics for HIV, HCV, HBV, and other infectiousdisease.

Stent implantation has become the new standard angioplasty procedure.However, in-stent restenosis remains the major limitation of coronarystenting. New approaches have been developed to target pharmacologicalmodulation of local vascular biology by local administration of drugs.This allows for drug applications at the precise site and time of vesselinjury. Numerous pharmacological agents with antiproliferativeproperties are currently under clinical investigation, includingactinomycin D, rapamycin or paclitaxel coated stents (Regar E., et al.,Br. Med. Bull. 59:227-248 (2001)). Therefore, apoptosis inducers, whichare antiproliferative, are useful as therapeutics for the prevention orreduction of in-stent restenosis.

Another important aspect of the present invention is the surprisingdiscovery that compounds of the present invention are potent and highlyefficacious activators of caspase-3, inhibitors of tubulinpolymerization, and inhibitors of topoisomerase even in drug resistantcancer cells, which enables these compounds to inhibit the growth andproliferation of drug resistant cancer cells, and to cause apoptosis andcell death in the drug resistant cancer cells. Specifically, thecompounds of the present invention are not substrates for the MDRtransporters such as Pgp-1 (MDR-1), MRP-1 and BCRP. This is particularlysurprising in view of the fact that almost all of the commerciallyavailable tubulin-interacting chemotherapeutics are substrates formultidrug resistance transporters (MDRs).

Multidrug resistance is the major cause of chemotherapy failure. Drugresistance is typically caused by ATP-dependent efflux of drug fromcells by ATP-binding cassette (ABC) transporters. In particular, the ABCtransporters ABCB1 (MDR-1, P glycoprotein); ABCC1 (MRP1); and ABCG2(BCRP, MXR) are typically over-expressed in drug resistant tumors andthus are implicated in drug resistance. In comparison to most standardanti-cancer drugs, which are not effective in killing drug resistantcancer cells, the compounds of the present invention are effective inkilling drug resistant cancer cells. Therefore, compounds of thisinvention are useful for the treatment of drug resistant cancer.

Thus, another aspect of the present invention is the application of themethods and compounds of the present invention as described above totumors that have acquired resistance to other anticancer drugs. In oneembodiment, a compound of the present invention is administered to acancer patient who has been treated with another anti-cancer drug. Inanother embodiment, a compound of the present invention is administeredto a patient who has been treated with and is not responsive to anotheranti-cancer drug or developed resistance to such other anti-cancercompound. In another embodiment, a compound of the present invention isadministered to a patient who has been treated with another anti-cancerdrug and is refractory to said other anti-cancer drug. The compounds ofthe present invention can be used in treating cancer in a patient who isnot responsive or is resistant to any other anti-cancer agent. Examplesof such other anti-cancer agent may include alkylating agents,antimitotic agents, topo I inhibitors, topo II inhibitors, RNA/DNAantimetabolites, EGFR inhibitors, angiogenesis inhibitors, tubulininhibitors (e.g., vinblastine, taxol (paclitaxel), and analoguesthereof), proteosome inhibitors, etc., some of the exemplary compoundsof which are provided above and are general known in the art, e.g.,melphalan, chlorambucil, cyclophosamide, ifosfamide, vincristine,mitoguazone, epirubicin, aclarubicin, bleomycin, mitoxantrone,elliptinium, fludarabine, octreotide, retinoic acid, tamoxifen, Gleevec®(imatinib mesylate) and alanosine. The compounds can be used in treatingpatients having any type of diseases responsive to the inhibition oftubulin or inhibition of topoisomerase (including but not limited to thetypes of cancer described above) who are not responsive or becomeresistant to another therapeutic agent, e.g., another anti-cancer agent.

Pharmaceutical compositions within the scope of this invention includeall compositions wherein the compounds of the present invention arecontained in an amount that is effective to achieve its intendedpurpose. While individual needs vary, determination of optimal ranges ofeffective amounts of each component is within the skill of the art.Typically, the compounds may be administered to animals, e.g., mammals,orally at a dose of 0.0025 to 50 mg/kg of body weight, per day, or anequivalent amount of the pharmaceutically acceptable salt thereof, to amammal being treated. Preferably, approximately 0.01 to approximately 10mg/kg of body weight is orally administered. For intramuscularinjection, the dose is generally approximately one-half of the oraldose. For example, a suitable intramuscular dose would be approximately0.0025 to approximately 25 mg/kg of body weight, and most preferably,from approximately 0.01 to approximately 5 mg/kg of body weight. If aknown cancer chemotherapeutic agent is also administered, it isadministered in an amount that is effective to achieve its intendedpurpose. The amounts of such known cancer chemotherapeutic agentseffective for cancer are well known to those skilled in the art.

The unit oral dose may comprise from approximately 0.01 to approximately50 mg, preferably approximately 0.1 to approximately 10 mg of thecompound of the invention. The unit dose may be administered one or moretimes daily, as one or more tablets, each containing from approximately0.1 to approximately 10 mg, conveniently approximately 0.25 to 50 mg ofthe compound or its solvates.

In a topical formulation, the compound may be present at a concentrationof approximately 0.01 to 100 mg per gram of carrier.

In addition to administering the compound as a raw chemical, thecompounds of the invention may be administered as part of apharmaceutical preparation containing suitable pharmaceuticallyacceptable carriers comprising excipients and auxiliaries, whichfacilitate processing of the compounds into preparations that may beused pharmaceutically. Preferably, the preparations, particularly thosepreparations which may be administered orally and that may be used forthe preferred type of administration, such as tablets, dragees, andcapsules, and also preparations that may be administered rectally, suchas suppositories, as well as suitable solutions for administration byinjection or orally, contain from approximately 0.01 to 99 percent,preferably from approximately 0.25 to 75 percent of active compound(s),together with the excipient.

Also included within the scope of the present invention are thenon-toxic pharmaceutically acceptable salts of the compounds of thepresent invention. Acid addition salts are formed by mixing a solutionof the compounds of the present invention with a solution of apharmaceutically acceptable non-toxic acid, such as hydrochloric acid,fumaric acid, maleic acid, succinic acid, acetic acid, citric acid,tartaric acid, carbonic acid, phosphoric acid, oxalic acid, and thelike. Basic salts are formed by mixing a solution of the compounds ofthe present invention with a solution of a pharmaceutically acceptablenon-toxic base, such as sodium hydroxide, potassium hydroxide, cholinehydroxide, sodium carbonate, Tris, N-methyl-glucamine and the like.

The pharmaceutical compositions of the invention may be administered toany animal, which may experience the beneficial effects of the compoundsof the invention. Foremost among such animals are mammals, e.g., humansand veterinary animals, although the invention is not intended to be solimited.

The pharmaceutical compositions of the present invention may beadministered by any means that achieve their intended purpose. Forexample, administration may be by parenteral, subcutaneous, intravenous,intramuscular, intraperitoneal, transdermal, buccal, intrathecal,intracranial, intranasal or topical routes. Alternatively, orconcurrently, administration may be by the oral route. The dosageadministered will be dependent upon the age, health, and weight of therecipient, kind of concurrent treatment, if any, frequency of treatment,and the nature of the effect desired.

The pharmaceutical preparations of the present invention aremanufactured in a manner, which is itself known, e.g., by means ofconventional mixing, granulating, dragee-making, dissolving, orlyophilizing processes. Thus, pharmaceutical preparations for oral usemay be obtained by combining the active compounds with solid excipients,optionally grinding the resulting mixture and processing the mixture ofgranules, after adding suitable auxiliaries, if desired or necessary, toobtain tablets or dragee cores.

Suitable excipients are, in particular: fillers, such as saccharides,e.g. lactose or sucrose, mannitol or sorbitol; cellulose preparationsand/or calcium phosphates, e.g. tricalcium phosphate or calcium hydrogenphosphate; as well as binders, such as starch paste, using, e.g., maizestarch, wheat starch, rice starch, potato starch, gelatin, tragacanth,methyl cellulose, hydroxypropylmethylcellulose, sodiumcarboxymethylcellulose, and/or polyvinyl pyrrolidone. If desired,disintegrating agents may be added, such as the above-mentioned starchesand also carboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar,or alginic acid or a salt thereof, such as sodium alginate. Auxiliariesare, above all, flow-regulating agents and lubricants, e.g., silica,talc, stearic acid or salts thereof, such as magnesium stearate orcalcium stearate, and/or polyethylene glycol. Dragee cores are providedwith suitable coatings which, if desired, are resistant to gastricjuices. For this purpose, concentrated saccharide solutions may be used,which may optionally contain gum arabic, talc, polyvinyl pyrrolidone,polyethylene glycol and/or titanium dioxide, lacquer solutions andsuitable organic solvents or solvent mixtures. In order to producecoatings resistant to gastric juices, solutions of suitable cellulosepreparations, such as acetylcellulose phthalate orhydroxypropymethyl-cellulose phthalate, are used. Dye stuffs or pigmentsmay be added to the tablets or dragee coatings, e.g., for identificationor in order to characterize combinations of active compound doses.

Other pharmaceutical preparations, which may be used orally includepush-fit capsules made of gelatin, as well as soft, sealed capsules madeof gelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules may contain the active compounds in the form of: granules,which may be mixed with fillers, such as lactose; binders, such asstarches; and/or lubricants, such as talc or magnesium stearate and,optionally, stabilizers. In soft capsules, the active compounds arepreferably dissolved or suspended in suitable liquids, such as fattyoils, or liquid paraffin. In addition, stabilizers may be added.

Possible pharmaceutical preparations, which may be used rectallyinclude, e.g., suppositories, which consist of a combination of one ormore of the active compounds with a suppository base. Suitablesuppository bases are, e.g., natural or synthetic triglycerides, orparaffin hydrocarbons. In addition, it is also possible to use gelatinrectal capsules, which consist of a combination of the active compoundswith a base. Possible base materials include, e.g., liquidtriglycerides, polyethylene glycols, or paraffin hydrocarbons.

Suitable formulations for parenteral administration include aqueoussolutions of the active compounds in water-soluble form, e.g.,water-soluble salts and alkaline solutions. In addition, suspensions ofthe active compounds as appropriate oily injection suspensions may beadministered. Suitable lipophilic solvents or vehicles include fattyoils, e.g., sesame oil, or synthetic fatty acid esters, e.g., ethyloleate or triglycerides or polyethylene glycol-400 (the compounds aresoluble in PEG-400), or cremophor, or cyclodextrins. Aqueous injectionsuspensions may contain substances which increase the viscosity of thesuspension include, e.g., sodium carboxymethyl cellulose, sorbitol,and/or dextran. Optionally, the suspension may also contain stabilizers.

In accordance with one aspect of the present invention, compounds of theinvention are employed in topical and parenteral formulations and areused for the treatment of skin cancer.

The topical compositions of this invention are formulated preferably asoils, creams, lotions, ointments and the like by choice of appropriatecarriers. Suitable carriers include vegetable or mineral oils, whitepetrolatum (white soft paraffin), branched chain fats or oils, animalfats and high molecular weight alcohol (greater than C₁₂). The preferredcarriers are those in which the active ingredient is soluble.Emulsifiers, stabilizers, humectants and antioxidants may also beincluded, as well as agents imparting color or fragrance, if desired.Additionally, transdermal penetration enhancers may be employed in thesetopical formulations. Examples of such enhancers are found in U.S. Pat.Nos. 3,989,816 and 4,444,762.

Creams are preferably formulated from a mixture of mineral oil,self-emulsifying beeswax and water in which mixture of the activeingredient, dissolved in a small amount of an oil, such as almond oil,is admixed. A typical example of such a cream is one which includesapproximately 40 parts water, approximately 20 parts beeswax,approximately 40 parts mineral oil and approximately 1 part almond oil.

Ointments may be formulated by mixing a solution of the activeingredient in a vegetable oil, such as almond oil, with warm softparaffin and allowing the mixture to cool. A typical example of such anointment is one which includes approximately 30% almond oil andapproximately 70% white soft paraffin by weight.

The following examples are illustrative, but not limiting, of the methodand compositions of the present invention. Other suitable modificationsand adaptations of the variety of conditions and parameters normallyencountered in clinical therapy and which are obvious to those skilledin the art are within the spirit and scope of the invention.

EXAMPLE 1

(2-Chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine

a) 2,4-Dichloroquinazoline: A suspension of 2,4-quinazolinedione (5.0 g,30.8 mmol) in neat phosphorylchloride (50 mL) was heated under refluxfor 18 h. The reaction mixture was concentrated under vacuum. The crudeproduct was purified by chromatography (Silica gel) using ethyl acetateand hexane (1:4) to give 2,4-dichloroquinazoline as white solid (4.8 g,96%). ¹H NMR (CDCl₃): 8.29 (ddd, J=8.4, 2.1 and 0.9 Hz, 1H), 8.04-8.00(m, 2H), 7.75 (ddd, J=8.1, 4.8 and 3.0 Hz, 1H).

b) (2-Chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine: Asolution of 2,4-dichloroquinazoline (300 mg, 1.51 mmol) and4-methoxy-N-methylaniline (248 mg, 1.81 mmol) in 5 ml isopropanol with adrop of concentrated HCl was stirred at room temperature for 8 h. Whiteprecipitates were observed in the reaction mixture. The reaction wasfiltered, and the solid was washed with isopropanol, and dried undervacuum to give white powder (260 mg, 87%). ¹H NMR (CDCl₃): 8.66 (dd,J=8.4 and 0.9 Hz, 1H), 7.75 (ddd, J=8.1, 7.5 and 0.9 Hz, 1H), 7.26-7.19(m, 3H), 7.14 (ddd, J=8.1, 7.5, 0.9 Hz, 1H), 7.06 (dd, J=6.9 and 2.4 Hz,2H), 6.75 (d, J=8.7 Hz, 1H), 3.91 (s, 3H), 3.81 (s, 3H).

EXAMPLE 2

(2-Chloro-quinazolin-4-yl)-(4-methyl-phenyl)-methyl-amine

The title compound was prepared from 2,4-dichloroquinazoline (250 mg,1.25 mmol) and 4-methyl-N-methylaniline (196 mg, 1.43 mmol) by aprocedure similar to example 1b and was isolated as white powder (210mg, 84%). ¹H NMR (CDCl₃): 8.69 (d, J=8.4 Hz, 1H), 7.75 (dd, J=8.1 and7.5 Hz, 1H), 7.39 (d, J=7.8 Hz, 2H), 7.25 (d, J=7.8 Hz, 2H), 7.13 (d,J=8.2 Hz, 1H), 6.74 (d, J=8.7 Hz, 1H), 3.81 (s, 3H), 2.49 (s, 3H).

EXAMPLE 3

(2-Chloro-quinazolin-4-yl)-(4-chloro-phenyl)-methyl-amine

The title compound was prepared from 2,4-dichloroquinazoline (60 mg,0.302 mmol) and 4-chloro-N-methylaniline (50 mg, 0.332 mmol) by aprocedure similar to example 1b and was isolated as white powder (30 mg,50%). ¹H NMR (CDCl₃): 8.66 (d, J=8.4 Hz, 1H), 7.78 (ddd, J=8.1, 7.5 and2.4 Hz, 1H), 7.57 (d, J=8.7 Hz, 2H), 7.28 (d, J=8.7 Hz, 2H), 7.19 (ddd,J=8.1, 7.5 and 2.4 Hz, 1H), 6.79 (d, J=8.4 Hz, 1H), 3.83 (s, 3H).

EXAMPLE 4

(2-Chloro-quinazolin-4-yl)-(4-nitro-phenyl)-methyl-amine

The title compound was prepared from 2,4-dichloroquinazoline (50 mg,0.251 mmol) and 4-nitro-N-methylaniline (46 mg, 0.302 mmol) by aprocedure similar to example 1b and was isolated as yellow powder (6 mg,12%). ¹H NMR (CDCl₃): 8.24 (d, J=8.7 Hz, 2H), 7.81 (dd, J=8.1, and 2.4Hz, 1H), 7.68 (ddd, J=8.1, 7.5 and 2.4 Hz, 1H), 7.28 (d, J=8.7 Hz, 2H),7.18 (ddd, J=8.1, 7.5 and 2.4 Hz, 1H), 7.07 (d, J=7.8 Hz, 1H), 3.75 (s,3H).

EXAMPLE 5

(2-Chloro-quinazolin-4-yl)-(4-trifluoromethoxy-phenyl)-methyl-amine

The title compound was prepared from 2,4-dichloroquinazoline (50 mg,0.251 mmol) and 4-trifluoromethoxy-N-methylaniline (20 μL, 0.302 mmol)by a procedure similar to example 1b and was isolated as white powder(22 mg, 44%). ¹H NMR (CDCl₃): 7.93 (dd, J=8.4, and 0.6 Hz, 1H),7.61(ddd, J=8.4, 4.5 and 1.2 Hz, 1H), 7.29-7.22 (m, 4H), 7.06 (ddd,J=8.4, 4.5 and 1.2 Hz, 1H), 6.91 (d, J=8.7 Hz, 1H), 3.65 (s, 3H).

EXAMPLE 6

(2-Chloro-quinazolin-4-yl)-phenyl-methyl-amine

The title compound was prepared from 2,4-dichloroquinazoline (50 mg,0.251 mmol) and N-methylaniline (20 μL, 0.301 mmol) by a proceduresimilar to example 1b and was isolated as white powder (40 mg, 80%). ¹HNMR (CDCl₃): 7.76 (dd, J=8.7, and 1.5 Hz, 1H), 7.56 (ddd, J=8.1, 6.6 and1.5 Hz, 1H), 7.46-7.35 (m, 3H), 7.24-7.20 (m, 2H), 6.98 (ddd, J=8.7, 6.6and 1.5 Hz, 1H), 6.90 (dd, J=8.7 and 1.5 Hz, 1H), 3.65 (s, 3H).

EXAMPLE 7

(2-Chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-amine

The title compound was prepared from 2,4-dichloroquinazoline (50 mg,0.251 mmol) and 4-methoxyaniline (45 mg, 0.326 mmol) by a proceduresimilar to example 1b and was isolated as off white powder (55 mg, 77%).¹H NMR (CDCl₃): 10.25 (s, 1H), 8.58 (d, J=8.4 Hz, 1H), 7.88 (t, J=7.2Hz, 1H), 7.71-7.63 (m, 4H), 7.03-6.99 (m, 2H), 3.79 (s, 3H).

EXAMPLE 8

(2-Chloro-quinazolin-4-yl)-(4-methyl-phenyl)-amine

The title compound was prepared from 2,4-dichloroquinazoline (50 mg,0.251 mmol) and 4-methylaniline (32 mg, 0.30 mmol) by a proceduresimilar to example 1b and was isolated as white powder (15 mg, 30%). ¹HNMR (CDCl₃): 7.97-7.89 (m, 3H), 7.71 (d, J=6.6 Hz, 2H), 7.64 (ddd,J=8.4, 6.6 and 2.1 Hz, 1H), 7.33 (d, J=6.6 Hz, 2H), 2.47 (s, 3H).

EXAMPLE 9

2-Chloro-4-(5-methoxyindol-1-yl)quinazoline

The title compound was prepared from 2,4-dichloroquinazoline (50 mg,0.251 mmol) and 5-methoxyindole (40 mg, 0.302 mmol) similar to example1b and was isolated as white powder (14 mg, 28%). ¹H NMR (CDCl₃): 8.91(s, 1H), 8.70(ddd, J=8.4, 2.8 and 1.5 Hz, 1H), 8.01 (ddd, J=8.4, 2.8 and1.5 Hz, 1H), 7.92 (dd, J=6.9 and 1.5 Hz, 1H), 7.87 (m, 1H), 7.74 (d,J=2.4 Hz, 1H), 7.61 (ddd, J=8.4, 6.9 and 1.2 Hz, 1H), 7.37 (d, J=9.0 Hz,1H), 6.97 (dd, J=9.0 and 2.4 Hz, 1H), 3.88 (s, 3H).

EXAMPLE 10

N²-Hydroxyl-N⁴-(4-methoxy-phenyl)-N⁴-methyl-quinazoline-2,4-diamine

A mixture of (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine(15 mg, 0.050 mmol) and hydroxylamine hydrochloride (6.7 mg, 0.10 mmol)in isopropanol was heated by microwave at 130° C. for 20 min. Thesolvent was evaporated under reduced pressure. The product was isolatedby preparative TLC as white solid (6 mg, 40%) using acetone:hexane (1:1)as eluent. ¹H NMR (CDCl₃): 7.65 (d, J=8.4 Hz, 1H), 7.47 (ddd, J=8.4, 6.9and 1.8 Hz, 1H), 7.08 (d, J=8.7Hz, 2H), 6.94 (d, J=8.7 Hz, 2H),6.88-6.75 (m, 2H), 3.86 (s, 3H), 3.48 (s, 3H).

EXAMPLE 11

N²-(2-Hydroxylethyl)-N⁴-(4-methoxy-phenyl)-N⁴-methyl-quinazoline-2,4-diamine

The title compound was prepared from(2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (15 mg, 0.050mmol) and 2-hydroxylethylamine (20 μL) by a procedure similar to example10 and was isolated as white solid (12 mg, 80%). ¹H NMR (CDCl₃): 7.43(ddd, J=8.4, 1.5 and 0.9 Hz, 1H), 7.35 (ddd, J=7.8, 3.3 and 1.5 Hz, 1H),7.12-7.06 (m, 2H), 6.92-6.90 (m, 2H), 6.84 (dd, J=8.4 and 1.5 Hz, 1H),6.66 (ddd, J=7.2, 6.3 and 1.5 Hz, 1H), 3.91-3.89 (m, 2H), 3.83 (s, 3H),3.69-3.65 (m, 2H), 3.48 (s, 3H).

EXAMPLE 12

N⁴-(4-Methoxy-phenyl)-N⁴-methyl-quinazoline-2,4-diamine

Title compound was prepared from(2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (10 mg, 0.033mmol) and 7 M ammonia in methanol (1 mL) by a procedure similar toexample 10 (5 mg, 50%). ¹H NMR (CDCl₃): 7.44 (m, 2H), 7.16 (m, 2H),6.96-6.95 (m, 2H), 6.88 (dd, J=8.4 and 1.5 Hz, 1H), 6.72 (ddd, J=8.7,6.6 and 1.8 Hz, 1H), 3.86 (s, 3H), 3.72 (s, 3H).

EXAMPLE 13

N²-(3,7-Dimethyl-octa-2,6-dienyl)-N⁴-(4-methoxy-phenyl)-N⁴-methyl-quinazoline-2,4-diamine

The title compound was prepared from(2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (45 mg, 0.151mmol) and 3,7-dimethyl-2,6-diene-octamine (60 μL, 0.301 mmol) by aprocedure similar to example 10 and was isolated as white powder (15 mg,33%). ¹H NMR (CDCl₃): 7.42 (d, J=8.1 Hz, 1H), 7.32 (ddd, J=8.7, 6.6 and1.5 Hz, 1H), 7.12-7.07 (m, 2H), 6.91-6.85 (m, 3H), 6.65 (ddd, J=8.7, 6.6and 1.5 Hz, 1H), 5.41 (t, J=7.5 Hz, 1H), 5.11 (ddd, J=6.6, 5.1 and 1.2Hz, 1H), 4.15 (d, J=6.9 Hz, 2H), 3.85 (s, 3H), 3.50 (s, 3H), 2.12-2.03(m, 4H), 1.75 (s, 3H), 1.70 (s, 3H), 1.61 (s, 3H).

EXAMPLE 14

N⁴-(4-Methoxy-phenyl)-N⁴-methyl-N²-(2-morpholin-4-yl-ethyl)-quinazoline-2,4-diamine

The title compound was prepared from(2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (10 mg, 0.033mmol) and 2-morpholin-4-yl-ethylamine (30 μL) by a procedure similar toexample 10 and was isolated as white powder (10 mg, 100%). ¹H NMR(CDCl₃): 7.42 (dd, J=8.7 and 1.2 Hz, 1H), 7.36 (ddd, J=8.1, 6.6 and 1.5Hz, 1H), 7.10-7.09 (m, 2H), 6.92-6.86 (m, 3H), 6.67 (ddd, J=8.1, 6.6 and1.4 Hz, 1H), 3.82 (s, 3H), 3.75-3.62 (m, 6H), 3.52 (s, 3H), 2.55-2.44(m, 6H).

EXAMPLE 15

(4-Methoxy-phenyl)-methyl-(2-morpholin-4-yl-quinazolin-4-yl)-amine

The title compound was prepared from(2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (15 mg, 0.050mmol) and morpholine (30 μL) by a procedure similar to example 10 andwas isolated as white powder (10 mg, 66%). ¹H NMR (CDCl₃): 7.46 (d,J=8.4 Hz, 1H), 7.35 (ddd, J=8.4, 6.6 and 1.5 Hz, 1H), 7.13-7.07 (m, 2H),6.91-6.85 (m, 3H), 6.67 (ddd, J=8.4, 6.6 and 1.5 Hz, 1H), 3.94-3.90 (m,4H), 3.85-3.81 (m, 7H), 3.52 (s, 3H).

EXAMPLE 16

N²-(3,7-Dimethyl-octa-2,6-dienyl)-N⁴-(4-methyl-phenyl)-N⁴-methyl-quinazoline-2,4-diamine

The title compound was prepared from(2-chloro-quinazolin-4-yl)-(4-methyl-phenyl)-methyl-amine (50 mg, 0.177mmol) and 3,7-dimethyl-2,6-diene-octamine (50 μL, 0.265 mmol) by aprocedure similar to example 10 and was isolated as white powder (7 mg,14%). ¹H NMR (CDCl₃): 7.45 (d, J=8.1 Hz, 1H), 7.35 (ddd, J=8.1, 6.6 and1.5 Hz, 1H), 7.16 (d, J=7.8 Hz, 2H), 7.06 (d, J=7.8 Hz, 2H), 6.91 (d,J=8.4 Hz, 1H), 6.66 (ddd, J=8.1, 6.6 and 1.5 Hz, 1H), 5.41 (dd, J=6.9and 5.7 Hz, 1H), 5.11 (dd, J=5.7 and 4.2 Hz, 1H), 4.15 (t, J=6.9 Hz,2H), 3.50 (s, 3H), 2.36 (s, 3H), 2.12-2.03 (m, 4H), 1.75 (s, 3H), 1.68(s, 3H), 1.61 (s, 3H).

EXAMPLE 17

N⁶-(4-Methoxy-phenyl)-N⁶-methyl-9H-purine-2,6-diamine

The title compound was prepared from 2-amino-6-chloro-9H-purine (100 mg,0.546 mmol) and 4-methoxy-N-methyl-aniline (127 mg, 0.656 mmol) by aprocedure similar to example 1b and was isolated as white powder (5 mg,5%). ¹H NMR (CDCl₃): 7.54 (s, 1H), 7.25 (d, J=8.7 Hz, 2H), 6.98 (d,J=8.7 Hz, 2H), 3.86 (s, 3H), 3.66 (s, 3H).

EXAMPLE 18

N²,N⁴-Dimethyl-N²,N⁴-diphenyl-quinazoline-2,4-diamine

The title compound was prepared from 2,4-dichloroquinazoline (50 mg,0.251 mmol) and N-methylaniline (40 μL, 0.401 mmol) by a proceduresimilar to example 1b and was isolated as white powder (33 mg, 66%). ¹HNMR (CDCl₃): 7.54 (dd, J=8.2 and 0.6 Hz, 1H), 7.45 (dd, J=8.4 and 1. Hz,1H), 7.44-7.29 (m, 6H), 7.21-7.10 (m, 4H), 6.86 (dd, J=8.4 and 0.9 Hz,1H), 6.67 (ddd, J=8.4, 7.2 and 1.1 Hz, 1H), 3.69 (s, 3H), 3.33 (s, 3H).

EXAMPLE 19

N²,N⁴-Bis(4-chloro-phenyl)-N²,N⁴-dimethyl-quinazoline-2,4-diamine

The title compound was prepared from 2,4-dichloroquinazoline (60 mg,0.3.02 mmol) and 4-chloro-N-methylaniline (72 mg, 0.513 mmol) by aprocedure similar to example 1b and was isolated as white powder (50 mg,83%). ¹H NMR (CDCl₃): 8.93 (d, J=8.4 Hz, 1H), 7.56 (t, J=7.5 Hz, 1H),7.47-7.44 (m, 4H), 7.32-7.27 (m, 2H), 7.18-7.14 (m, 2H), 6.95 (t, J=7.5Hz, 1H), 6.67 (d, J=8.4 Hz, 1H), 4.02 (s, 3H), 3.25 (s, 3H).

EXAMPLE 20

(2-Chloro-6,7-dimethoxyquinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine

A mixture of 2,4-dichloro-6,7-dimethoxyquinazoline (100 mg, 0.386 mmol),4-methoxy-N-methylaniline (55 mg, 0.401mmol) and sodium acetate (60 mg,0.732 mmol) in tetrahydrofuran (5 mL) and water (2.5 mL) was stirred atroom temperature for 48 h. The reaction mixture was evaporated todryness and the residue was crystallized using ethanol/water andisolated as white solid (60 mg, 60%). ¹-H NMR (CDCl₃): 8.19 (s, 1H),7.32-7.26 (m, 2H), 7.09-7.07 (m, 2H), 6.16 (s, 1H), 4.03 (s, 3H), 3.87(s, 3H), 3.75 (s, 3H), 3.32 (s, 3H).

EXAMPLE 21

(2-Chloro-6,7-dimethoxyquinazolin-4-yl)-(4-methoxy-phenyl)-amine

The title compound was prepared from2,4-dichloro-6,7-dimetoxyquinazoline (100 mg, 0.386 mmol) and4-methoxyaniline (49 mg, 0.386 mmol) by a procedure similar to example1b and was isolated as white powder (10 mg, 10%). ¹H NMR (CDCl₃): 8.10(s, 1H), 7.70-7.68 (m, 2H), 7.23 (s, 1H), 6.96-6.94 (m, 2H), 4.07 (s,3H), 3.99 (s, 3H), 3.85 (s, 3H).

EXAMPLE 22

(2-Chloro-6,7-dimethoxyquinazolin-4-yl)-(4-methyl-phenyl)-methyl-amine

The title compound was prepared from2,4-dichloro-6,7-dimetoxyquinazoline (100 mg, 0.386 mmol) andN-methyl-p-tolylamine (49 mg, 0.386 mmol) by a procedure similar toexample 1b and was isolated as white powder (8 mg, 8%). ¹H NMR (CDCl₃):7.27 (d, J=8.4 Hz, 2H), 7.15 (d, J=8.4 Hz, 2H), 7.08 (s, 1H), 6.26 (s,1H), 3.92 (s, 3H), 3.61 (s, 3H), 3.28 (s, 3H), 2.37 (s, 3H).

EXAMPLE 23

6,7-Dimethoxy-N⁴-(4-methoxy-phenyl)-N⁴-methyl-N²-(2-morpholin-4-yl-ethyl)-quinazoline-2,4-diamine

The title compound was prepared from(2-chloro-6,7-dimethoxyquinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine(50 mg, 0.139 mmol) and 2-morpholin-4-yl-ethylamine (25 μL, 0.167 mmol)by a procedure similar to example 10 and was isolated as white powder(27 mg, 54%). ¹H NMR (CDCl₃): 7.21 (d, J=8.4 Hz, 2H), 7.00 (d, J=8.4 Hz,2H), 6.93 (s, 1H), 6.13 (s, 1H), 3.95 (s, 3H), 3.84 (s, 3H), 3.77-3.74(m, 4H), 3.71-3.66 (m, 2H), 3.60 (s, 3H), 3.25 (s, 3H), 2.70 (t, J=7.2Hz, 2H), 2.59-2.56 (m, 4H).

EXAMPLE 24

6,7-Dimethoxy-N²-(3,7-dimethyl-octa-2,6-dienyl)-N⁴-(4-methoxy-phenyl)-N⁴-methyl-quinazoline-2,4-diamine

The title compound was prepared from(2-chloro-6,7-dimethoxyquinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine(60 mg, 0.167 mmol) and 3,7-dimethyl-2,6-diene-octamine (50 mg, 0.424mmol) by a procedure similar to example 10 and was isolated as whitepowder (68 mg, 85%). ¹H NMR (CDCl₃): 7.15 (d, J=8.4 Hz, 2H), 6.91 (d,J=8.4 Hz, 2H), 6.85 (s, 1H), 6.29 (s, 1H), 5.41 (dd, J=6.9 and 6.0 Hz,1H), 5.12 (ddd, J=6.9, 5.1 and 4.2 Hz, 1H), 4.69 (t, J=4.5 Hz, 1H), 4.12(t, J=5.7 Hz, 2H), 3.91 (s, 3H), 3.79 (s, 3H), 3.49 (s, 3H), 3.30 (s,3H), 2.13-2.05 (m, 4H), 1.75 (s, 3H), 1.69 (s, 3H), 1.61 (s, 3H).

EXAMPLE 25

(5,6,7,8-Tetrahydro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine

a) 4-Chloro-5,6,7,8-tetrahydroquinazoline: The title compound wasprepared from 5,6,7,8-tetrahydro-4-quinazolinone (50 mg, 0.301 mmol) andphosphorylchloride (5 mL) by a procedure similar to example la and wasisolated as off white solid (20 mg, 40%). ¹H NMR (CDCl₃): 8.60 (s, 1H),2.75 (m, 2H), 1.76 (m, 4H), 1.53 (m, 2H).

b) (5,6,7,8-Tetrahydro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine:The title compound was prepared from4-chloro-5,6,7,8-tetrahydroquinazoline (20 mg, 0.099 mmol) and4-methoxy-N-methylaniline (16 mg, 0.111 mmol) by a procedure similar toexample 1b and was isolated as white powder (25 mg, 83%). ¹H NMR(CDCl₃): 8.60 (s, 1H), 7.02-6.96 (m, 2H), 6.87-6.82 (m, 2H), 3.83 (s,3H), 3.39 (s, 3H), 2.75 (t, J=6.6 Hz, 2H), 1.76 (m, 4H), 1.53 (m, 2H).

EXAMPLE 26

(2-Chloro-quinazolin-4-yl)-(4-methoxy-benzyl)-methyl-amine

The title compound was prepared from 2,4-dichloroquinazoline (50 mg,0.251 mmol) and N-methyl-4-methoxybenzylamine (45 mg, 0.302 mmol) by aprocedure similar to example 1b and was isolated as white powder (30 mg,60%). ¹H NMR (CDCl₃): 7.93 (dd, J=8.4 and 1.2 Hz, 1H), 7.78 (dd, J=8.4and 1.5 Hz, 1H), 7.68 (ddd, J=8.4, 7.5 and 1.5 Hz, 1H), 7.34-7.26 (m,3H), 6.96-6.92 (m, 2H), 4.94 (s, 2H), 3.83 (s, 3H), 3.31 (s, 3H).

EXAMPLE 27

(2-Chloro-quinazolin-4-yl)-pyridin-4-yl-amine

To a stirred suspension of 2,4-dichloroquinazoline (42 mg, 0.21 mmol)and 4-aminopyridine (21 mg, 0.22 mmol) in 3 mL of anhydrous isopropanolwas added a drop of concentrated HCl and the mixture was stirredovernight. Solid precipitates were observed and the mixture wasfiltered. The solid was washed with cold isopropanol and dried to givethe title compound as white solid (38 mg, 0.13 mmol, 61%). ¹H NMR(DMSO-d₆): 8.60 (d, J=7.5 Hz, 2H), 8.18-8.20 (m, 2H), 8.07-8.10 (m, 1H),7.90-7.96 (m, 1H), 7.18 (d, J=7.8 Hz, 2H).

EXAMPLE 28

(2-Chloro-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl)-amine

A mixture of 2,4-dichloroquinazoline (61 mg, 0.31 mmol),5-amino-2-methoxy pyridine (40 mg, 0.32 mmol) and sodium acetate (38 mg,0.46 mmol) in 3 mL of solvent (THF:water/1:1) was stirred at 60° C. for45 min. The reaction mixture was diluted with 25 mL of ethyl acetate. Itwas washed with saturated NaCl, dried over anhydrous MgSO₄, filtered andconcentrated. The crude product was purified by chromatography (40%ethyl acetate/hexanes) on silica gel to give the title compound (86 mg,0.30 mmol, 98%). ¹H NMR (CDCl₃): 8.38 (d, J=3.0 Hz, 1H), 8.07 (dd, J=8.7and 3.0 Hz, 1H), 7.89-7.79 (d, J=8.4 Hz, 1H), 7.86 (m, 2H), 7.59-7.53(m, 2H), 6.84 (d, J=8.7 Hz, 1H), 3.96 (s, 3H).

EXAMPLE 29

(2-Chloro-quinazolin-4-yl)-(2,3-dimethoxy-phenyl)-amine

The title compound was prepared from 2,4-dichloroquinazoline and2,3-dimethoxyaniline by a procedure similar to example 28 (84% yield).¹H NMR (CDCl₃): 8.57 (s, broad, 1H), 8.38 (d, J=8.4 Hz, 1H), 7.77-7.86(m, 3H), 7.55-7.61 (m, 1H), 7.15 (t, J=8.7 Hz, 1H), 6.73-6.75 (m, 1H),4.00 (s, 3H), 3.91 (s, 3H).

EXAMPLE 30

(2-Chloro-quinazolin-4-yl)-(2,4-dimethoxy-phenyl)-amine

The title compound was prepared from 2,4-dichloroquinazoline and2,4-dimethoxyaniline by a procedure similar to example 28 (92% yield).¹H NMR (CDCl₃): 8.59 (d, J=8.7 Hz, 1H), 8.22 (s, broad, 1H), 7.75-7.81(m, 3H), 7.52 (ddd, J=8.4, 6.6 and 2.1 Hz, 1H), 6.52-6.59 (m, 2H), 3.95(s, 3H), 3.82 (s, 3H).

EXAMPLE 31

(2-Chloro-quinazolin-4-yl)-(2,5-dimethoxy-phenyl)-amine

The title compound was prepared from 2,4-dichloroquinazoline and2,5-dimethoxyaniline by a procedure similar to example 28 (98% yield).¹H NMR (CDCl₃): 8.59 (d, J=3.0 Hz, 1H), 8.53 (s, broad, 1H), 7.78-7.87(m, 3H), 7.57 (ddd, J=8.4, 6.6 and 1.8 Hz, 1H), 6.88 (d, J=9.0 Hz, 1H),6.60 (dd, J=8.7 and 3.0 Hz, 1H), 3.97 (s, 3H), 3.87 (s, 3H).

EXAMPLE 32

(2-Chloro-quinazolin-4-yl)-(3-methoxy-phenyl)-amine

The title compound was prepared from 2,4-dichloroquinazoline and3-methoxyaniline by a procedure similar to example 28 (80% yield). ¹HNMR (CDCl₃): 7.79-7.87 (m, 3H), 7.54-7.62 (m, 3H), 7.20-7.35 (m, 3H),6.76 (dd, J=8.4 and 2.1 Hz, 1H), 3.87 (s, 3H).

EXAMPLE 33

(2-Chloro-quinazolin-4-yl)-(2-methoxy-phenyl)-amine

The title compound was prepared from 2,4-dichloroquinazoline and2-methoxyaniline by a procedure similar to example 28 (35% yield). ¹HNMR (CDCl₃): 8.76-8.79 (m, 1H), 8.50 (s, broad, 1H), 7.77-7.88 (m, 3H),7.54-7.59 (m, 1H), 7.09-7.13 (m, 2H), 6.95-6.99 (m, 2H), 4.00 (s, 3H).

EXAMPLE 34

(4-Methoxy-phenyl)-methyl-quinazolin-4-yl-amine

The title compound was prepared from 4-chloroquinazoline and4-methoxy-N-methylaniline by a procedure similar to example 28 (79%yield). ¹H NMR (CDCl₃): 8.81 (s, 1H), 7.81 (d, J=8.1Hz, 1H), 7.57 (ddd,J=8.1, 5.4 and 2.7 Hz, 1H), 7.09-7.14 (m, 2H), 7.03-7.06 (m, 2H),6.9-6.93 (m, 2H).

EXAMPLE 35

(4-Methyl-phenyl)-methyl-quinazolin-4-yl-amine

The title compound was prepared from 4-chloroquinazoline and4-methyl-N-methylaniline by a procedure similar to example 28 (80%yield). ¹H NMR (CDCl₃): 8.23 (s, 1H), 7.82 (d, J=8.4 Hz, 1H), 7.57 (ddd,J=8.4, 6.3 and 1.8 Hz, 1H), 7.17-7.20 (m, 2H), 7.00-7.10 (m, 4H), 3.61(s, 3H), 2.39 (s, 3H).

EXAMPLE 36

(2-Chloro-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl)-methyl-amine

To a solution of(2-chloro-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl)-amine (19.4 mg,0.068 mmol) in 1 mL of DMF cooled at 0° C. was added methyl iodide (100uL, 1.61 mmol), followed by sodium hydride (60% oil suspension, 5 mg,0.13 mmol). The mixture was stirred at 0° C. for 1 h, then allowed towarm to room temperature and stirred for 1 h. The reaction mixture wasquenched by adding 50 uL of water, diluted with 25 mL of ethyl acetate,washed with water (25 mL×3), saturated NaCl, dried over anhydrous MgSO₄,filtered and concentrated. The residue was purified by chromatography(20% ethyl acetate/hexanes) to give the title compound (14.3 mg, 0.048mmol, 70%). ¹H NMR (CDCl₃) 8.06 (d, J=2.7 Hz, 1H), 7.57-7.79 (m, 1H),7.60 (ddd, J=8.1, 6.6 and 1.2 Hz, 1H), 7.44 (dd, J=8.7 and 2.7 Hz, 1H),7.09 (ddd, J=8.1, 6.6 and 1.2 Hz, 1H), 6.99-7.02 (m, 1H), 6.82 (dd,J=8.7 and 0.6 Hz, 1H), 3.97 (s, 3H), 3.61 (s, 3H).

EXAMPLE 37

(2-Chloro-quinazolin-4-yl)-isopropyl-(4-methoxy-phenyl)-amine

a) Isopropyl-(4-methoxy-phenyl)-amine: To a stirred solution ofp-methoxy-aniline (443 mg, 3.60 mmol) and acetone (265 uL, 3.61 mmol) in10 mL of anhydrous methanol at room temperature was added a drop ofglacial acetic acid followed by NaCNBH₃ (226 mg, 3.60 mmol) portion wiseover 0.5 h. The reaction mixture was then stirred for 3 h at roomtemperature. The solvents were removed under vacuum, and the residue wasdissolved in 50 mL of ethyl acetate. The solution was washed with 5%NaHCO₃, saturated NaCl, dried over anhydrous MgSO4, filtered andconcentrated. The crude was purified by chromatography (10% ethylacetate/hexanes) to give the title compound (287 mg, 1.92 mmol, 48%). ¹HNMR (CDCl₃): 6.77 (d, J=8.7 Hz, 2H), 6.57 (d, J=6.7 Hz, 2H), 3.74 (s,3H), 3.54 (m, 1H, J=6.3), 2.94 (s, broad, 1H), 1.92 (d, J=6.3 Hz, 6H).

b) (2-Chloro-quinazolin-4-yl)-isopropyl-(4-methoxy-phenyl)-amine: Thetitle compound was prepared from isopropyl-(4-methoxy-phenyl)-amine and2,4-dichloroquinazoline by a procedure similar to example 27 (51%yield). ¹H NMR (DMSO-d₆): 8.30-8.34 (m, 1H), 8.17-8.22 (m, 1H),8.05-8.08 (m, 1H), 7.90-7.96 (m, 1H), 7.77 (d, J=8.1Hz, 2H), 1.09 (d,J=8.4 Hz, 2H), 3.62 (m, 1H), 3.79 (s, 3H), 1.24 (d, J=6.0 Hz, 6H).

EXAMPLE 38

(2-Chloro-quinazolin-4-yl)-cyclohexyl-(4-methoxy-phenyl)-amine

a) Cyclohexyl-(4-methoxy-phenyl)-amine: The title compound was preparedfrom cyclohexanone and p-methoxy aniline by a procedure similar toexample 37a (60% yield). ¹H NMR (CDCl₃): 6.76 (d, J=9.0 Hz, 2H), 6.57(d, J=9.0 Hz, 2H), 3.75 (s, 3H), 3.16 (m, 1H), 2.34 (m, 1H), 1.61-1.89(m, 5H), 1.05-1.42 (m, 5H).

b) (2-Chloro-quinazolin-4-yl)-cyclohexyl-(4-methoxy-phenyl)-amine: Thetitle compound was prepared from cyclohexyl-(4-methoxy-phenyl)-amine and2,4-dichloroquinazoline by a procedure similar to example 27 (93%yield). ¹H NMR (DMSO-d₆): 8.32 (dd, J=8.4 and 1.5 Hz, 1H), 8.22 (ddd,J=8.4, 7.5 and 1.5 Hz, 1H), 8.05-8.09 (m, 1H), 7.93 (ddd, J=8, 6.9, 0.9Hz, 1H), 7.45 (d, J=8.7 Hz, 2H), 7.08 (d, J=8.7 Hz, 2H), 3.27-3.34 (m,1H), 1.89-1.92 (m, 2H), 1.73-1.76 (m, 2), 1.36-1.62 (m, 3H), 1.07-1.28(m, 3H).

EXAMPLE 39

(2-Chloro-quinazolin-4-yl)-(2,3-dimethoxy-phenyl)-methyl-amine

The title compound was prepared from(2-chloro-quinazolin-4-yl)-(2,3-dimethoxy-phenyl)-amine and methyliodide by a procedure similar to example 36 (71% yield). ¹H NMR (CDCl₃):7.74 (d, J=8.4 Hz, 1H), 7.53-7.59 (m, 1H), 7.12 (t, J=8.4 Hz, 1H),6.94-7.01 (m, 3H), 6.87 (dd, J=8.1 and 1.5 Hz, 1H), 3.89 (s, 3H), 3.56(s, 3H).

EXAMPLE 40

(2-Chloro-quinazolin-4-yl)-ethyl-(4-methoxy-phenyl)-amine

The title compound was prepared from(2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-amine and ethyl iodide bya procedure similar to example 36 (58% yield). ¹H NMR (CDCl₃): 7.69-7.72(m, 1H), 7.53 (ddd, J=8.1, 6.9 and 1.5 Hz, 1H), 7.09-7.14 (m, 2H),6.94-6.70 (m, 3H), 6.83-6.87 (m, 1H), 4.13 (q, J=7.2 Hz, 2H), 3.87 (s,1H), 1.30 (t, J=6.9 Hz, 3H).

EXAMPLE 41

(2-Chloro-quinazolin-4-yl)-(2,4-dimethoxy-phenyl)-methyl-amine

The title compound was prepared from(2-chloro-quinazolin-4-yl)-(2,4-dimethoxy-phenyl)-amine and methyliodide by a procedure similar to example 36 (91% yield). ¹H NMR (CDCl₃):7.70-7.73 (m, 1H), 7.54 (ddd, J=8.7, 6.3 and 2.1 Hz, 1H), 7.10 (d, J=8.7Hz, 1H), 6.93-7.23 (m, 2H), 6.50-6.57 (m, 2H), 3.87 (s, 3H), 3.67 (s,3H), 3.52 (s, 3H).

EXAMPLE 42

(2-Chloro-quinazolin-4-yl)-(2,5-dimethoxy-phenyl)-methyl-amine

The title compound was prepared from(2-chloro-quinazolin-4-yl)-(2,5-dimethoxy-phenyl)-amine and methyliodide by a procedure similar to example 36 (78% yield). ¹H NMR (CDCl₃):7.72-7.75 (m, 1H), 7.56 (ddd, J=8.4, 5.7 and 2.1 Hz, 1H), 6.98-7.00 (m,2H), 6.92-6.92 (m, 2H), 6.78-6.79 (m, 1H), 3.75 (s, 3H), 3,58 (s, 3H),3.56 (s, 3H).

EXAMPLE 43

(2-Chloro-quinazolin-4-yl)-(3-methoxy-phenyl)-methyl-amine

The title compound was prepared from(2-chloro-quinazolin-4-yl)-(3-methoxy-phenyl)-amine and methyl iodide bya procedure similar to example 36 (60% yield). ¹H NMR (CDCl₃): 7.74-7.76(m, 1H), 7.57 (ddd, J=8.4, 6.0 and 1.8 Hz, 1H), 7.32 (t, J=7.8 Hz, 1H),6.98-7.03 (m, 2H), 6.89 (dd, J=8.1 and 2.4 Hz, 1H), 6.75-6.81 (m, 2H),3.65 (s, 3H), 3.37 (s, 3H).

EXAMPLE 44

(2-Chloro-quinazolin-4-yl)-(2-methoxy-phenyl)-methyl-amine

The title compound was prepared from(2-chloro-quinazolin-4-yl)-(2-methoxy-phenyl)-amine and methyl iodide bya procedure similar to example 36 (72% yield). ¹H NMR (CDCl₃): 7.72 (d,J=8.1 Hz, 1H), 7.54 (ddd, J=8.4, 6.6 and 1.5 Hz, 1H), 7.20 (dd, J=8.4and 1.8 Hz, 1H), 6.87-7.04 (m, 4H), 3.67 (s, 3H), 3.56 (s, 3H).

EXAMPLE 45

(2-Chloro-quinazolin-4-yl)-cyclopentyl-(4-methoxy-phenyl)-amine

a) Cyclopentyl-(4-methoxy-phenyl)-amine: The title compound was preparedfrom cyclopentanone and p-methoxy aniline by a procedure similar toexample 37a (68% yield). ¹H NMR (CDCl₃): 6.78 (d, J=8.7 Hz, 2H), 6.57(d, J=8.7 Hz, 2H), 3.74 (s, 3H), 3.18 (m, 1H), 2.23 (m, 1H), 1.82-2.01(m, 2H), 1.52-1.73 (m, 4H), 1.38-1.49 (m, 2H).

b) (2-Chloro-quinazolin-4-yl)-cyclopentyl-(4-methoxy-phenyl)-amine: Thetitle compound was prepared from cyclopentyl-(4-methoxy-phenyl)-amineand 2,4-dichloroquinazoline by a procedure similar to example 27 (39%yield). ¹H NMR (CDCl₃): 8.31 (dd, J=8.7 and 1.3 Hz, 1H), 8.12 (ddd,J=8.4, 7.2 and 1.3 Hz, 1H), 8.12-8.08 (m, 1H), 7.93 (ddd, J=8.3, 7.2 and1.3 Hz, 1H), 7.41 (d, J=8.4 Hz, 2H), 7.11 (d, J=8.7 Hz, 2H), 3.24-3.33(m, 1H), 2.22-2.01 (m, 2H), 1.51-1.75 (m, 4H), 1.32-1.49 (m, 2H).

EXAMPLE 46

N²-[2-(1H-Imidazol-4-yl)-ethyl]-N⁴-(4-methoxy-phenyl)-N⁴-methyl-quinazoline-2,4-diamine

The title compound was prepared from(2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methylamine (10 mg, 0.033mmol) and histamine hydrochloride (16 mg, 0.10) by a procedure similarto example 10 and was isolated as white solid (7 mg, 70%). ¹H NMR(CDCl₃): 7.52 (s, 1H), 7.49 (brd, J=3.9 Hz, 2H), 7.20-7.15 (m, 2H),7.03-6.96 (m, 3H), 6.83 (ddd, J=8.4, 4.5 and 3.9 Hz, 1H), 6.66 (d, J=8.7Hz, 1H), 3.88 (s, 3H), 3.85 (t, J=6.6 Hz, 2H), 3.63 (s, 3H), 3.03 (t,J=6.6 Hz, 2H).

EXAMPLE 47

N²-(3-Dimethylamino-propyl)-N⁴-(4-methoxy-phenyl)-N⁴-methyl-quinazoline-2,4-diamine

The title compound was prepared from(2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (15 mg, 0.050mmol) and N¹,N¹-dimethyl-propane-1,3-diamine (16 μl, 0.070 mmol) by aprocedure similar to example 10 and was isolated as white powder (11 mg,73%). ¹H NMR (CDCl₃): 7.43 (dd, J=8.4 and 1.2 Hz, 1H), 7.34 (ddd, J=7.8,6.6 and 1.2 Hz, 1H), 7.11-7.07 (m, 2H), 6.89-6.86 (m, 3H), 6.65 (ddd,J=8.1, 6.6 and 1.2 Hz, 1H), 3.82 (s, 3H), 3.61 (t, J=6.9 Hz, 2H), 3.49(s, 3H), 2.41 (t, J=6.9 Hz, 2H), 2.28 (s, 6H), 1.89 (m, 2H).

EXAMPLE 48

N²-(2-Hydroxyethyl)-N⁴-(6-methoxypyridin-3-yl)-N⁴-methyl-quinazoline-2,4-diamine

The title compound was prepared from(2-chloro-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl)-methyl-amine (12 mg,0.040 mmol) and ethanolamine (28 μl) by a procedure similar to example10 and was isolated as off white solid (8 mg, 66%). ¹H NMR (CDCl₃): 8.03(brd, J=3.0 Hz, 1H), 7.47-7.35 (m, 3H), 6.91 (brd, J=8.7 Hz, 1H),6.78-6.73 (m, 2H), 5.56 (brs, 1H), 3.94 (s, 3H), 3.93-3.90 (m, 2H),3.70-3.56 (m, 2H), 3.48 (s, 3H).

EXAMPLE 49

N⁴-(6-methoxypyridin-3-yl)-N⁴-methyl-quinazoline-2,4-diamine

The title compound was prepared from(2-chloro-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl)-methylamine (10 mg,0.030 mmol) and 7 M ammonia in methanol (1 mL) by a procedure similar toexample 10 (3 mg, 30%). ¹H NMR (CDCl₃): 8.04 (dd, J=2.9, 0.6 Hz, 1H),7.49-7.43 (m, 2H), 7.39 (dd, J=5.7 and 2.7 Hz, 1H), 6.92 (brd, J=8.4 Hz,1H), 6.85-6.78 (m, 2H), 5.65 (s, 2H), 3.96 (s, 3H), 3.54 (s, 3H).

EXAMPLE 50

N²-(2-Hydroxyethyl)-N⁴-(4-methoxy-phenyl)-N⁴-methyl-6,7-dimethoxyquinazoline-2,4-diamine

The title compound was prepared from(2-Chloro-6,7-dimethoxyquinazolin-4-yl)-(4-methoxy-phenyl)-amine (26 mg,0.079 mmol) and ethanolamine (30 μl) by a procedure similar to example10 and was isolated as white powder (14 mg, 54%). ¹H NMR (CDCl₃): 7.14(dd, J=6.6 and 2.1 Hz, 2H), 6.91 (d, J=6.6 and 2.1 Hz, 2H), 6.81 (s,1H), 6.25 (s, 1H), 3.90 (s, 3H), 3.92-3.88 (m, 2H), 3.80 (s, 3H),3.69-3.65 (m, 2H), 3.49 (s, 3H), 3.28 (s, 3H).

EXAMPLE 51

(2-Chloro-9H-purin-6-yl)-(4-methoxy-phenyl)-methyl-amine

The title compound was prepared from 2,6-dichloro-9H-purine (50 mg,0.265) and 4-methoxy-N-methylaniline (40 mg, 0.291 mmol) by a proceduresimilar to example 1b and was isolated as off white powder (10 mg, 20%).¹H NMR (CDCl₃): 7.81 (s, 1H), 7.37 (d, J=8.4 Hz, 2H), 7.04 (d, J=8.4 Hz,2H), 3.93 (s, 3H), 3.77 (s, 3H).

EXAMPLE 52

(2-Chloro-quinazolin-4-yl)-(4-methylcarboxyphenyl)-methyl-amine

The title compound was prepared from 2,4-dichloroquinazoline (30 mg,0.152 mmol) and 4-methylamino-benzoic acid methyl ester (27 mg, 0.167mmol) by a procedure similar to example 1b and was isolated as off whitepowder (25 mg, 83%). ¹H NMR (CDCl₃): 8.08-8.04 (m, 2), 7.81 (ddd, J=8.4,5.4 and 1.2 Hz, 1H), 7.62 (ddd, J=8.7, 3.9 and 1.8 Hz, 1H), 7.26-7.21(m, 2H), 7.06 (ddd, J=8.4, 7.8 and 0.9 Hz, 1H), 6.99 (ddd, J=7.5, 1.2and 0.9 Hz, 1H), 3.94 (s, 3H), 3.70(s, 3H).

EXAMPLE 53

(2-methoxy-quinazolin-4-yl)-(4-methoxyphenyl)-methylamine

To a solution of(2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (50 mg, 0.167mmol) in 2 ml methanol was added sodium methoxide (500 μl, 25% by wt. inmethanol). The solution was stirred at 80° C. for 1 h, and it wasdiluted with 50 ml ethylacetate. The solution was washed with water,dried and concentrated. The product was purified using small silicacolumn and isolated as off white solid (22 mg, 54%). ¹H NMR (CDCl₃):7.89 (d, J=8.4 Hz, 1H), 7.53 (ddd, J=8.7, 5.4 and 2.4 Hz, 1H), 7.19-7.14(m, 2H), 6.99-6.93 (m, 2H), 6.90-6.85 (m, 2H), 4.14 (s, 3H), 3.86 (s,3H), 3.64 (s, 3H).

EXAMPLE 54

(2-Chloro-quinazolin-4-yl)-(4-hydroxyphenyl)-methylamine

To a solution of(2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (100 mg,0.334 mmol) in 30 ml dichloromethane cooled at −20° C. was added slowly60 μl of BBr₃ (0.668 mmol). The reaction mixture was stirred at −20° C.for 2 h then it was warmed to room temperature. It was stirred another 2h at this temperature. The reaction mixture was diluted with ethylacetate (50 ml) and washed with cold 5% sodium bicarbonate. The organicphase was dried and concentrated. The residue was purified by a smallsilica column using ethyl acetate and hexane (1:3) as eluents to givethe product (57 mg, 57%). ¹H NMR (CDCl₃): 7.65-7.56 (m, 2H), 7.04-6.87(m, 5H), 3.59 (s, 3H).

EXAMPLE 55

(2-Fluoromethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine

a) 2-Fluoromethyl-quinazolin-4(3H)-one: To a solution of 2-amino-benzoicacid methyl ester (151 mg, 1 mmol) and fluoro-acetonitrile (0.14 ml, 2.5mmol) in dioxane (5 ml) at room temperature was added concentrated HCl(0.05 ml) dropwise. The mixture was heated at 80° C. for 24 h and thencooled to room temperature. The resulting solid was collected anddissolved in water (10 ml), and the solution was neutralized withsaturated aqueous NaHCO₃ to pH 7. The solution was extracted by ethylacetate. The extracts were evaporated, and the residue was purified bycolumn chromatography on silica gel with ethyl acetate and hexane (1:1)as eluent, yielding 70 mg (39%) of the title compound.

b) (2-Fluoromethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine: Asuspension of 2-fluoromethyl-quinazolin-4(3H)-one (70 mg, 0.39 mmol) inphosphoryl chloride (2 ml) and N,N-dimethylaniline (0.035 ml, 0.27 mmol)was heated under reflux for 12 hours. The reaction mixture was pouredonto ice and the precipitate was collected by filtration, then washedand dried to give 4-chloro-2-fluoromethyl-quinazoline, which was useddirectly for the next reaction. To a solution of4-chloro-2-fluoromethyl-quinazoline with (4-methoxy-phenyl)-methylamine(160 mg, 1.2 mmol) in isopropyl alcohol (5 ml) was added concentratedHCl (0.05 ml) and the solution was stirred at room temperatureovernight. The solution was neutralized with saturated aqueous NaHCO₃,and was extracted by ethyl acetate. The extracts were evaporated, andthe residue was purified by column chromatography on silica gel withethyl acetate and hexane (1:1) as eluent, yielding 11 mg (9.5%) of thetitle compound. ¹H NMR (CDCl₃): 7.87-7.84 (m, 1H), 7.60-7.54 (m, 1H),7.14-7.10 (m, 2H), 7.04-7.01 (m, 2H), 6.95-6.91 (m, 2H), 5.60 (s, 1H),5.44 (s, 1H), 3.85 (s, 3H), 3.60 (s, 3H).

EXAMPLE 56

(2-Chloro-6-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine

a) 6-Methyl-quinazoline-2,4-dione: To a suspension of 2-amino-5-methylbenzoic acid (0.758 g, 5 mmol) and potassium cyanate (0.673 g, 8.3 mmol)in water (20 mL) was added acetic acid (0.5 mL). The mixture was stirredat room temperature for 24 h. A white solid was collected by vacuumfiltration, washed with water, and dried in vacuo (0.736 g, 84%): ¹H NMR(DMSO-d₆) 9.90 (br s, 1H), 8.27 (d, J=8.4 Hz, 1H), 7.70 (d, J=1.8 Hz,1H), 7.29 (dd, J=2.4, 8.7 Hz, 1H), 6.50 (br s, 1H), 2.25 (s, 3H).

b)(2-Chloro-6-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine:The above 6-methyl-quinazoline-2,4-dione (201 mg, 1.14 mmol) andN,N-dimethylaniline (0.2 mL) were refluxed in phosphorus oxychloride (5mL) under argon overnight. The solvent was removed by distillation underreduced pressure. The purple residue was dissolved in isopropanol (10mL). N-methyl-p-anisidine (201 mg, 1.465 mmol) was added. The mixturewas stirred at room temperature overnight. The solvent was evaporatedand the residue was purified by column chromatography (SiO₂,EtOAc:hexanes 5-25%) to give the product as a light yellow solid (62 mg,17%): ¹H NMR (CDCl₃) 7.62 (d, J=8.7 Hz, 1H), 7.38 (dd, J=1.8, 8.7 Hz,1H), 7.16-7.10 (m, 2H), 6.89-6.86 (m, 2H), 6.63 (s, 1H), 3.86 (s, 3H),3.60 (s, 3H), 2.09 (s, 3H).

Compounds of EXAMPLE 57-64 were prepared similar to Example 56.

EXAMPLE 57

(2-Chloro-7-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine

a) 7-Methyl-quinazoline-2,4-dione: White solid: ¹H NMR (DMSO-d₆) 10.07(br s, 1H), 8.24 (s, 1H), 7.79 (d, J=8.1 Hz, 1H), 6.78 (dd, J=0.6, 9.0Hz, 1H), 6.54 (br s, 1H), 2.30 (s, 3H).

b) (2-Chloro-7-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine:Light yellow solid: ¹H NMR (CDCl₃) 7.51 (m, 1H), 7.16-7.10 (m, 2H),6.96-6.91 (m, 2H), 6.83 (dd, J=1.8, 8.7 Hz, 1H), 6.78 (d, J=8.7 Hz, 1H),3.85 (s, 3H), 3.59 (s, 3H), 2.38 (s, 3H).

EXAMPLE 58

(2-Chloro-5-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine

a) 5-Methyl-quinazoline-2,4-dione: Off-white solid: ¹H NMR (CDCl₃) 11.04(s, 2H), 7.45 (t, J=7.8 Hz, 1H), 7.01 (d, J=7.8 Hz, 1H), 6.94 (d, J=7.5Hz, 1H), 2.65 (s, 3H).

b) (2-Chloro-5-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine:Light yellow solid: ¹H NMR (CDCl₃) 7.64-7.61 (m, 1H), 7.54 (dd, J=7.2,8.4 Hz, 1H), 6.99-6.96 (m, 1H), 6.75-6.68 (m, 4H), 3.75 (s, 3H), 3.63(s, 3H), 2.11 (s, 3H).

EXAMPLE 59

(2-Chloro-8-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine

a) 8-Methyl-quinazoline-2,4-dione: Light brown solid: ¹H NMR (DMSO-d₆)11.43 (s, 1H), 10.50 (s, 1H), 7.86 (d, J=8.1 Hz, 1H), 7.58 (d, J=7.2 Hz,1H), 7.19 (t, J=7.8 Hz, 1H), 2.43 (s, 3H).

b) (2-Chloro-8-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine:¹H NMR (CDCl₃) 7.42-7.39 (m, 1H), 7.14-7.04 (m, 2H), 6.94-6.87 (m, 3H),6.84 (dd, J=1.5, 8.4 Hz, 1H), 3.84 (s, 3H), 3.60 (s, 3H), 2.63 (s, 3H).

EXAMPLE 60

(2,6-Dichloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine

a) 6-Chloro-quinazoline-2,4-dione: white solid: ¹H NMR (DMSO-d₆) 11.44(s, 1H), 11.28 (s, 1H), 7.81 (d, J=2.1 Hz, 1H), 7.69 (dd, J=9.0, 2.1 Hz,1H), 7.19 (d, J=9.0 Hz, 1H).

b) (2,6-Dichloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine:

Yellow solid: ¹H NMR (CDCl₃) 7.66 (d, J=8.7 Hz, 1H), 7.49 (dd, J=2.1,8.7 Hz, 1H), 7.18-7.12 (m, 2H), 7.02-6.96 (m, 2H), 6.78 (dd, J=0.6, 2.1Hz, 1H), 3.88 (s, 3H), 3.61 (s, 3H).

EXAMPLE 61

6-Chloro-N²,N⁴-bis-(4-methoxy-phenyl)-N²,N⁴-dimethyl-quinazoline-2,4-diamine

The title compound was isolated from the reaction of Example 60. Yellowsolid: ¹H NMR (CDCl₃) 7.41 (d, J=9.0 Hz, 1H), 7.35-7.30 (m, 2H), 7.29(d, J=2.4 Hz, 1H), 7.26 (t, J=1.5 Hz, 1H), 7.09-7.04 (m, 2H), 6.94-6.80(m, 5H), 6.72 (d, J=2.4 Hz, 1H), 3.84 (s, 3H), 3.83 (s, 3H), 3.62 (s,3H), 3.27 (s, 3H).

EXAMPLE 62

(2,7-Dichloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine

a) 7-Chloro-quinazoline-2,4-dione: White solid: ¹H NMR (DMSO-d₆) 11.42(s, 1H), 11.26 (s, 1H), 7.88 (d, J=8.7 Hz, 1H), 7.22 (dd, J=1.2, 8.1 Hz,1H), 7.18 (d, J=2.1 Hz, 1H).

b) (2,7-Dichloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine: Lightyellow solid: ¹H NMR (CDCl₃) 7.70 (d, J=2.4 Hz, 1H), 7.16-7.11 (m, 2H),6.98-6.92 (m, 3H), 6.80 (d, J=9.3 Hz, 1H), 3.86 (s, 3H), 3.60 (s, 3H).

EXAMPLE 63

5-Chloro-N²,N⁴-bis-(4-methoxy-phenyl)-N²,N⁴-dimethyl-quinazoline-2,4-diamine

a) 5-Chloro-quinazoline-2,4-dione: White solid: ¹H NMR (DMSO-d₆) 11.28(s, 2H), 7.55td (td, J=8.4, 0.6 Hz, 1H), 7.19 (d, J=7.8 Hz, 1H), 7.12(d, J=8.4 Hz, 1H).

b)5-Chloro-N²,N⁴-bis-(4-methoxy-phenyl)-N²,N⁴-dimethyl-quinazoline-2,4-diamine:Yellow solid: ¹H NMR (CDCl₃) 7.43 (d, J=8.4 Hz, 1H), 7.32-7.26 (m, 3H),6.93-6.88 (m, 2H), 6.81 (dd, J=1.2, 7.2 Hz, 1H), 6.75-6.65 (m, 4H), 3.83(s, 3H), 3.73 (s, 3H), 3.61 (s, 3H), 3.33 (s, 3H).

EXAMPLE 64

(5-Chloro-2-isopropoxy-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine

The title compound was isolated from the reaction of Example 63. Whitesolid: ¹H NMR (CDCl₃) 7.45-7.36 (m, 2H), 7.26-7.21 (m, 2H), 7.13 (dd,J=2.1, 6.9 Hz, 1H), 6.94-6.89 (m, 2H), 5.09 (m, 1H), 3.85 (s, 3H), 3.57(s, 3H), 1.30 (d, J=6.3 Hz, 6H).

EXAMPLE 65

(Isoquinolin-1-yl)-(4-methoxy-phenyl)-methyl-amine

A mixture of 1-chloroisoquinoline (50 mg, 0.31 mmol) and(4-methoxy-phenyl)-methyl amine (300 mg, 2.2 mmol) was heated in asealed tube at 140° C. overnight. The crude product was purified bychromatography (5-6% ethyl acetate/hexanes) on silica gel to give thetitle compound (46 mg, 0.17 mmol, 57%). ¹H NMR (CDCl₃): 8.22 (d, 1H,5.7), 7.68 (d, 1H, J=8.1), 7.62 (d, 1H, J=8.7), 7.47 (ddd, 1H, J=0.9,6.9, 8.1), 7.24 (d, 1H, J=6.0), 7.19 (ddd, 1H, J=1.5, 6.9, 8.7), 6.94(m, 2H), 6.79 (m, 2H), 3.76 (s, 3H), 3.52 (s, 3H).

EXAMPLE 66

(4-Methoxy-phenyl)-methyl-(quinolin-4-yl)-amine

A mixture of 4-chloroquinoline (50 mg, 0.31 mmol) and(4-methoxy-phenyl)-methyl amine (300 mg, 2.2 mmol) was heated in asealed tube at 140° C. overnight. The crude product was purified bychromatography (20-40% ethyl acetate/hexanes) on silica gel to give thetitle compound (60 mg, 0.23 mmol, 74%). ¹H NMR (CDCl₃): 8.77 (d, 1H,J=5.1), 8.00-8.04 (m, 1H), 7.61-7.64 (m, 1H), 7.55 (ddd, 1H, J=1.5, 6.9,8.4), 7.22 (ddd, 1H, J=1.5, 6.9, 8.1), 6.99 (d, 1H, J=4.8), 6.92 (m,2H), 6.89 (m, 2H), 3.77 (s, 3H), 3.43 (s, 3H).

EXAMPLE 67

(2-Chloro-quinazolin-4-yl)-(3,4-methylenedioxyphenyl)-methyl-amine

a) (2-Chloro-quinazolin-4-yl)-(3,4-methylenedioxyphenyl)-amine: Thetitle compound was prepared from 3,4-methylenedioxyphenylamine and2,4-dichloroquinazoline by a procedure similar to example 1b and wasisolated as solids (45% yield). ‘H NMR (CDCl₃): 7.81-7.83 (m, 3H),7.51-7.56 (m, 2H), 7.44 (d, 1H, J=2.1), 6.98 (dd, 1H, J=2.1, 8.1), 6.82(d, 1H, J=8.1), 6.01 (s, 2H).

b). (2-Chloro-quinazolin-4-yl)-(3,4-methylenedioxyphenyl)-methyl-amine:The title compound was prepared from(2-chloro-quinazolin-4-yl)-(3,4-methylenedioxyphenyl)-amine by aprocedure similar to example 36 and was isolated as solids (66% yield).¹H NMR (CDCl₃): 7.73-7.76 (m, 1H), 7.58 (m, 1H), 7.07 (m, 2H), 6.82 (d,1H, J=8.4), 6.72 (m, 1H), 6.68 (m, 1H), 6.06 (s, 2H), 3.59 (s, 3H).

Compounds of EXAMPLE 68-70 were prepared similar to Example 67.

EXAMPLE 68

(2-Chloro-quinazolin-4-yl)-(3,4-dimethoxy-phenyl)-methyl-amine

a) (2-Chloro-quinazolin-4-yl)-(3,4-dimethoxy-phenyl)-amine: ¹H NMR(CDCl₃): 7.77-7.86 (m, 3H), 7.51-7.60 (m, 3H), 7.12 (dd, 1H, J=2.4,8.4), 6.90 (d, 1H, J=8.4), 3.94 (s, 3H), 3.91 (s, 3H).

b). (2-Chloro-quinazolin-4-yl)-(3,4-dimethoxy-phenyl)-methyl-amine: ¹HNMR (CDCl₃): 7.72-7.75 (m, 1H), 7.57 (ddd, 1H, J=1.5, 6.6, 8.4), 7.01(ddd, 1H, J=1.2, 6.9, 8.7), 6.88-6.96 (m, 2H), 6.73-6.81 (m, 2H), 3.94(s, 3H), 3.80 (s, 3H), 3.63 (s, 3H).

EXAMPLE 69

(2-Chloro-quinazolin-4-yl)-(4-phenoxy-phenyl)-methyl-amine

a) (2-Chloro-quinazolin-4-yl)-(4-phenoxy-phenyl)-amine: ¹H NMR (CDCl₃):7.78-7.87 (m, 3H), 7.68-7.74 (m, 2H), 7.60 (s, broad, 1H), 7.56 (ddd,1H, J=3.3, 9.9, 12.0), 7.33-7.39 (m, 2H), 7.03-7.16 (m, 5H).

b) (2-Chloro-quinazolin-4-yl)-(4-phenoxy-phenyl)-methyl amine: ¹H NMR(CDCl₃): 7.74-7.77 (m, 1H), 7.59 (ddd, 1H, J=1.5, 6.6, 8.4), 7.36-7.42(m, 2H), 7.10-7.20 (m, 3H), 7.03-7.10 (m, 5H), 6.97-7.00 (m, 1H), 3.64(s, 3H).

EXAMPLE 70

(2-Chloro-quinazolin-4-yl)-(4-propoxy-phenyl)-methyl-amine

a) (2-Chloro-quinazolin-4-yl)-(4-propoxy-phenyl)-amine: ¹H NMR (CDCl₃):7.76-7.84 (m, 3H), 7.52-7.62 (m, 4H), 6.95 (m, 2H), 3.94 (t, 2H, J=6.6),1.83 (hex, 2H, J=7.2), 1.05 (t, 3H, J=7.5)

b) (2-Chloro-quinazolin-4-yl)-(4-propoxy-phenyl)-methyl-amine: ¹H NMR(CDCl₃): 7.71-7.74 (m, 1H), 7.55 (ddd, 1H, J=1.5, 6.9, 8.4), 7.10-7.16(m, 2H), 7.00 (ddd, 1H, J=1.5, 6.9, 8.4), 6.91-6.96 (m, 3H), 3.96 (t,2H, J=6.6), 1.84 (hex, 2H, J=7.5), 1.08 (t, 3H, J=7.5).

EXAMPLE 71

4-(4-Methoxy-phenoxy)-quinazoline

To a stirred solution of 4-methoxyphenol (75 mg, 0.60 mmol) and4-chloro-quinazoline (125 mg, 76 mmol) in 3 mL of DMF was added sodiumhydride (60% oil suspension, 30 mg, 0.75 mmol) at 0° C., then thereaction mixture was allowed to warm to room temperature and stirred for5 h. The reaction was quenched by adding 50 uL of water and diluted with25 mL of ethyl acetate. It was washed with water (25 mL×3), saturatedNaCl, dried over anhydrous MgSO₄, filtered and concentrated. The residuewas purified by chromatography (25% ethyl acetate/hexanes) to give thetitle compound (134 mg, 0.53 mmol, 89%). ¹H NMR (CDCl₃): 8.78 (s, 1H),8.38 (m, 1H), 7.89-8.02 (m, 2H), 7.67 (m, 1H), 7.19 (m, 1H), 7.00 (m,1H), 3.86 (s, 3H).

EXAMPLE 72

(4-Methoxy-phenyl)-methyl-(2-methyl-quinazolin-4-yl)-amine hydrochloride

a) 4-Chloro-2-methyl-quinazoline: A stirred suspension of2-methyl-4(3H)-quinazolinone (5 g, 31.2 mmol) in POCl₃ (100 mL) washeated at 120° C. for 3 h. The excess POCl₃ was removed under vacuum,then to the residue was added crushed ice and 200 mL of saturatedNaHCO₃, and the mixture was extracted with ethyl acetate (200 mL×2). Thecombined extracts were washed with water, saturated NaCl, dried overanhydrous MgSO₄, filtered and concentrated. The crude product waspurified by column chromatography (5-8% ethyl acetate/hexane) to givethe title compound (2.5 g, 14.0 mmol, 45%). ¹H NMR (CDCl₃): 8.21-8.25(m, 1H), 7.89-7.99 (m, 2H), 7.66 (ddd, 1H, J=1.8, 6.6, 8.7), 2.87 (s,3H).

b) (4-Methoxy-phenyl)-methyl-(2-methyl-quinazolin-4-yl)-aminehydrochloride: The title compound was prepared from4-chloro-2-methyl-quinazoline (2.31 g, 12.9 mmol) and (4-methoxyphenyl)-methyl-amine (2.0 g, 14.6 mmol) by a procedure similar toexample 1b and was isolated as solids (2.90 g, 9.18 mmol, 71%). ¹H NMR(CDCl₃): 8.53 (dd, 1H, J=0.6, 8.1), 7.7 (ddd, 1H, J=1.2, 7.2, 8.4), 7.22(m, 2H), 7.13 (ddd, 1H, J=1.2, 7.2, 8.7), 7.05 (m, 2H), 6.76 (d, 1H,J=8.7), 3.91 (s, 3H), 3.78 (s, 3H), 2.96 (s, 3H).

EXAMPLE 73

(2-Chloromethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine

a) 2-Chloromethyl-quinazolin-4(3H)-one: To a solution of 2-amino-benzoicacid methyl ester (0.26 ml, 2 mmol) and chloro-acetonitrile (0.16 ml,4.0 mmol) in dioxane (8 ml) at room temperature was added concentratedHCl (1.0 ml) dropwise. The mixture was heated at 80° C. for 24 h andthen cooled to room temperature. The resulting solid was collected anddissolved in water (10 ml), and the solution was neutralized with 2 NNaOH aqueous to pH 7. The precipitation was collected by filtration,then washed with water and dried to give 309 mg (79.6%) of the titlecompound.

b) (2-Chloromethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine: Amixture of 2-chloromethyl-quinazolin-4(3H)-one (256 mg, 1.32 mmol),phosphoryl chloride (1.23 ml, 13.2 mmol) and N,N-dimethylaniline (0.34ml, 2.64 mmol) in chloroform (10 ml) was heated under reflux for 4 h.The reaction mixture was poured onto ice and extracted by ethyl acetate.The solvent was evaporated, and the residue was purified by columnchromatography on silica gel with acetate and hexane (1:1) as eluent,yielding 180 mg of 4-chloro-2-chloromethyl-quinazoline. The intermediate(170 mg, 0.80 mmol) and (4-methoxy-phenyl)-methylamine (131.7 mg, 0.96mmol) in isopropyl alcohol (5 ml) with concentrated HCl (0.05 ml) wasstirred at room temperature overnight. The precipitation was formed andcollected by filtration, then washed and dried to give 231 mg (92%) ofthe title compound. ¹H NMR (CDCl₃): 7.82 (d, J=8.7 Hz, 1H), 7.59-7.53(m, 1H), 7.15-7.12 (m, 2H), 7.03-7.00 (m, 2H), 6.95-6.91 (m, 2H), 4.73(s, 2H), 3.85 (s, 3H), 3.62 (s, 3H).

EXAMPLE 74

(2-Ethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine

The title compound was prepared in three steps by a procedure similar toExample 73. ¹H NMR (CDCl₃): 7.76 (d, J=8.4 Hz, 1H), 7.55-7.49 (m, 1H),7.13-7.09 (m, 2H), 7.03-6.89 (m, 4H), 3.83 (s, 3H), 3.60 (s, 3H), 2.97(q, J=7.5 Hz, 2H), 1.44 (t, J=7.8 Hz, 3H).

EXAMPLE 75

(2-Methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-amine

The title compound was prepared from 4-chloro-2-methyl-quinazoline (108mg, 0.605 mmol) and 4-methoxy-phenylamine (89.4 mg, 0.73 mmol) by aprocedure similar to Example 72b. ¹H NMR (DMSO-d₆): 11.28 (brs, 1H),8.73 (d, J=8.4 Hz, 1H), 8.06 (t, J=7.5 Hz, 1H), 7.85-7.78 (m, 2H), 7.66(d, J=9 Hz, 2H), 7.06 (d, J=8.7 Hz, 2H), 3.81 (s, 3H), 2.60 (s, 3H).

EXAMPLE 76

(2-Hydroxymethyl-quinazolin-4-yl)-4-methoxy-phenyl)-methyl-amine

To a solution of(2-chloromethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-aminehydrochloride salt (67 mg, 0.19 mmol) in 1,4-dioxane (3 ml) was added 2N NaOH aqueous (1 ml). The mixture was heated at 80° C. for 24 h andthen was cooled to room temperature. The reaction mixture was dilutedwith ethyl acetate, then was washed with water and dried with NaSO₄. Thesolvent was evaporated, and the residue was purified by columnchromatography on silica gel with acetate and hexane (1:1) as eluent,yielding 25 mg of title compound (44%). ¹H NMR (CDCl₃): 7.78-7.75 (m,1H), 7.59-7.53 (m, 1H), 7.15-7.12 (m, 2H), 7.02-7.00 (m, 2H), 6.94-6.91(m, 2H), 4.79 (s, 2H), 3.85 (s, 3H), 3.59 (s, 3H).

EXAMPLE 77

(2-Dimethylaminomethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine

The title compound was prepared from(2-chloromethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine anddimethylamine by a procedure similar to Example 76. ¹H NMR (DMSO-d₆):7.71 (d, J=8.7 Hz, 1H), 7.60 (t, J=8.4 Hz, 1H), 7.20 (d, J=8.4 Hz, 2H),7.09 (t, J=8.1 Hz, 1H), 7.00-6.96 (m, 3H), 3.78 (s, 3H), 3.63 (s, 2H),3.50 (s, 3H), 2.33 (s, 6H).

EXAMPLE 78

(4-Difluoromethoxy-phenyl)-(2-methyl-quinazolin-4-yl)-amine

A mixture of 4-chloro-2-methyl-quinazoline (450 mg, 2.52 mmol),4-difluoromethoxy-phenylamine (0.32 ml, 2.52 mmol) and sodium acetate(248.07 mg, 3.02 mmol) in 6 mL of solvent (THF:water=1:1) was stirred at70° C. for 1 h. The reaction mixture was diluted with 30 mL of ethylacetate. It was washed with brine, dried over anhydrous Na₂SO₄, filteredand concentrated. The crude product was purified by chromatography onsilica gel with acetate and hexane (1:5) as eluent, yielding 713 mg oftitle compound (94%). ¹H NMR (CDCl₃): 7.87-7.76 (m, 5H), 7.51 (t, J=8.4Hz, 1H)), 7.40 (brs, 1H), 7.19 (d, J=8.7 Hz, 2H), 6.76-6.27 (threesingle peaks, 1H), 2.71 (s, 3H).

EXAMPLE 79

(3-Fluoro-4-methoxy-phenyl)-(2-methyl-quinazolin-4-yl)-amine

The title compound was prepared from 4-chloro-2-methyl-quinazoline (150mg, 0.84 mmol), 3-fluoro-4-methoxy-phenylamine (118.5 mg, 0.84 mmol) bya procedure similar to example 78. ¹H NMR (CDCl₃): 7.89-7.75 (m, 4H),7.53-7.48 (m, 1H)), 7.38-7.34 (m, 2H), 7.0 (t, J=8.7 Hz, 1H), 3.92 (s,3H), 2.71 (s, 3H).

EXAMPLE 80

(4-Isopropoxy-phenyl)-(2-methyl-quinazolin-4-yl)-amine

The title compound was prepared from 4-chloro-2-methyl-quinazoline (100mg, 0.56 mmol), 4-isopropoxy-phenylamine (84.66 mg, 0.56 mmol) by aprocedure similar to example 78. ¹H NMR (CDCl₃): 7.84-7.72 (m, 3H),7.70-7.66 (m, 2H)), 7.50-7.45 (m, 1H), 7.30 (brs, 1H), 6.96-6.93 (m,2H), 4.59-4.51 (m, 1H), 2.68 (s, 3H), 1.36 (d, J=6.3 Hz, 6H).

EXAMPLE 81

(4-Ethyl-phenyl)-(2-methyl-quinazolin-4-yl)-amine

The title compound was prepared from 4-chloro-2-methyl-quinazoline (100mg, 0.56 mmol), 4-ethyl-phenylamine (0.07 ml, 0.56 mmol) by a proceduresimilar to example 78. ¹H NMR (CDCl₃): 7.85-7.78 (m, 2H), 7.76-7.71 (m,3H)), 7.49 (t, J=7.5 Hz, 1H), 7.36 (brs, 1H), 7.24 (s, 2H), 2.70-2.69(m, 5H), 1.26 (t, J=7.5 Hz, 3H).

EXAMPLE 82

(2-Methyl-quinazolin-4-yl)-(2,4,6-trimethoxy-phenyl)-amine

The title compound was prepared from 4-chloro-2-methyl-quinazoline (89.3mg, 0.5 mmol), 2,4,6-trimethoxy-phenylamine (91.6 mg, 0.5 mmol) by aprocedure similar to example 78. ¹H NMR (CDCl₃): 7.86 (d, J=8.4 Hz, 1H),7.80 (d, J=8.4 Hz, 1H), 7.71 (t, J=6.6 Hz, 1H), 7.41 (t, J=8.1 Hz, 1H),6.81 (brs, 1H), 6.25 (s, 2H), 3.87 (s, 3H), 3.79 (s, 6H), 2.57 (s, 3H).

EXAMPLE 83

(4-Methoxy-phenyl)-(2-phenyl-quinazolin-4-yl)-methyl-amine

The title compound was prepared from(4-methoxy-phenyl)-(2-phenyl-quinazolin-4-yl)-amine (51 mg, 0.16 mmol)and methyl iodide (0.07 ml, 1.09 mmol) by a procedure similar to Example36. ¹H NMR (CDCl₃): 8.64-8.61 (m, 2H), 7.90 (d, J=8.4 Hz, 1H), 7.59-7.48(m, 4H), 7.18-7.14 (m, 2H), 7.08-6.98 (m, 2H), 6.94-6.91 (m, 2H), 3.85(s, 3H), 3.73 (s, 3H).

EXAMPLE 84

(4-Difluoromethoxy-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine

The title compound was prepared from(4-difluoromethoxy-phenyl)-(2-methyl-quinazolin-4-yl)-amine (710 mg,2.36 mmol) and methyl iodide (1.03 ml, 16.52 mmol), by a proceduresimilar to Example 36 (40.8% yield). ¹H NMR (CDCl₃): 7.77 (dd, J=8.4 Hz,J=0.9 Hz, 1H), 7.59-7.53 (m, 1H), 7.17-7.10 (m, 4H), 7.06-6.99 (m, 2H),6.78 (d, J=0.6 Hz, 0.25H), 6.54 (d, J=0.9 Hz, 0.5H), 6.29 (d, J=0.9 Hz,0.25H), 3.62 (s, 3H), 2.75 (s, 3H).

EXAMPLE 85

(3-Fluoro-4-methoxy-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine

The title compound was prepared from(3-fluoro-4-methoxy-phenyl)-(2-methyl-quinazolin-4-yl)-amine (250 mg,0.88 mmol) and methyl iodide (0.39 ml, 6.18 mmol) by a procedure similarto example 36. ¹H NMR (CDCl₃): 7.76 (d, J=8.4 Hz, 1H), 7.59-7.53 (m,1H), 7.09-6.82 (m, 5H), 3.91 (s, 3H), 3.58 (s, 3H), 2.73 (s, 3H).

EXAMPLE 86

(4-Isopropoxy-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine

The title compound was prepared from(4-isopropoxy-phenyl)-(2-methyl-quinazolin-4-yl)-amine (164.3 mg, 0.56mmol) and methyl iodide (0.25 ml, 3.92 mmol) by a procedure similar toexample 36. ¹H NMR (CDCl₃): 7.73 (d, J=7.8 Hz, 1H), 7.54-7.49 (m, 1H),7.10-6.86 (m, 6H), 4.57-4.52 (m, 1H), 3.58 (s, 3H), 2.72 (s, 3H), 1.36(d, J=6 Hz, 6H).

EXAMPLE 87

(4-Ethyl-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine

The title compound was prepared from(4-ethyl-phenyl)-(2-methyl-quinazolin-4-yl)-amine (122 mg, 0.46 mmol)and methyl iodide (0.2 ml, 3.25 mmol) by a procedure similar to example36. ¹H NMR (CDCl₃): 7.74 (d, J=8.1 Hz, 1H), 7.54-7.49 (m, 1H), 7.19 (d,J=8.4 Hz, 2H), 7.09-6.92 (m, 4H), 3.61 (s, 3H), 2.73-2.63 (m, 5H), 1.26(d, J=7.5 Hz, 3H).

EXAMPLE 88

(2-Methyl-quinazolin-4-yl)-(2,4,6-trimethoxy-phenyl)-methyl-amine

The title compound was prepared from(2-methyl-quinazolin-4-yl)-(2,4,6-trimethoxy-phenyl)-amine (56 mg, 0.17mmol) and methyl iodide (0.1 ml, 1.6 mmol) by a procedure similar toexample 36. ¹H NMR (CDCl₃): 7.70 (d, J=8.4 Hz, 1H), 7.49 (t, J=7.8 Hz,1H), 7.09 (d, J=8.7 Hz, 1H), 6.93 (t, J=8.1 Hz, 1H), 6.18 (s, 2H), 3.86(s, 3H), 3.63 (s, 6H), 3.44 (s, 3H), 2.70 (s, 3H).

Compounds of Example 89-90 were prepared by a procedure similar toExample 56.

EXAMPLE 89

(2,8-Dichloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine

a) 8-Chloro-1H-quinazoline-2,4-dione: White solid: ¹H NMR (DMSO-d₆)11.47 (s, 1H), 10.77 (s, 1H), 7.88 (m, 1H), 7.78 (m, 1H), 7.18 (m, 1H).

b) (2,8-Dichloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine:Off-white solid: ¹H NMR (CDCl₃) 7.66 (dd, J=2.7, 6.3 Hz, 1H), 7.14-7.10(m, 2H), 6.97-6.89 (m, 4H), 3.86 (s, 3H), 3.62 (s, 3H).

EXAMPLE 90

(2,5-Dichloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine

a) 5-Chloro-1H,3H-quinazoline-2,4-dione: White solid: ¹H NMR (DMSO-d₆)11.28 (s, 2H), 7.55 (m, 1H), 7.19 (d, J=7.8 Hz, 1H), 7.12 (d, J=8.4 Hz,1H).

b) (2,5-Dichloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine:Yellow solid: ¹H NMR (CDCl₃) 7.67 (m, 1H), 7.52 (m, 1H), 7.16 (m, 1H),6.80-6.69 (m, 4H), 3.76 (s, 3H), 3.65 (s, 3H).

EXAMPLE 91

(5-Methoxy-2-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine

a) 5-Methoxy-2-methyl-quinazolin-4-ol: To a suspension of2-amino-6-methoxy-benzoic acid (305 mg, 1.82 mmol) and4-N,N-dimethylaminopyridine (20 mg, 0.16 mmol) in DMF/toluene (2:6 mL)at 0° C. was added triethylamine (1.1 mL, 7.9 mmol) followed by slowaddition of acetyl chloride (0.40 mL, 5.6 mmol) under argon.

The suspension was stirred at rt for 19 h. Ammonium acetate (0.62 g, 8.0mmol) was added and the reaction mixture was further stirred at 90° C.for 5 h. The solid was collected by filtration, washed with water, anddried to give an off-white solid (103 mg, 30%): ¹H NMR (CDCl₃) 10.69 (s,1H), 7.66 (t, J=8.4 Hz, 1H), 7.25 (d, J=8.4 Hz, 1H), 6.49 (d, J=8.4 Hz,1H), 4.01 (s, 3H), 2.53 (s, 3H).

b) (5-Methoxy-2-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine:The title compound was prepared by a procedure similar to that ofExample 56b as white solid: ¹H NMR (CDCl₃) 7.51 (t, J=8.4 Hz, 1H), 7.35(dd, J=0.9, 8.4 Hz, 1H), 6.85-6.80 (m, 2H), 6.85-6.72 (m, 2H), 6.56 (dd,J=0.9, 7.8 Hz, 1H), 3.75 (s, 3H), 3.60 (s, 3H), 3.25 (s, 3H), 2.68 (s,3H).

EXAMPLE 92

(4-Methoxy-phenyl)-(2-methyl-pyrido[2,3-d]pyrimidin-4-yl)-methyl-amine

a) 2-Methyl-pyrido[2,3-d]pyrimidin-4-ol: To a solution of2-amino-nicotinic acid (277 mg, 2 mmol), 4-N,N-dimethylaminopyridine (20mg, 0.16 mmol), triethylamine (1.1 mL, 7.9 mmol) in DMF (2 mL) was addedacetyl chloride (0.35 mL, 4.9 mmol) slowly at 0° C. under argon. Thewhite precipitate was formed immediately. The mixture was then heated at90° C. for 3.5 h, then ammonium acetate (0.601 g, 7.8 mmol) was added.The mixture was stirred for 1 h, cooled to rt and diluted with water (20mL). It was extracted with EtOAc (2×50 mL), and the extracts were driedover MgSO₄, and evaporated. The crude was purified by columnchromatography (SiO₂, EtOAc:MeOH/0-10%) to give an off-white solid (47mg, 16%): ¹H NMR (DMSO-d₆) 11.40 (s, 1H), 9.01 (dd, J=2.1, 4.8 Hz, 1H),8.61 (dd, J=2.4, 8.1 Hz, 1H), 7.44 (dd, J=4.8, 8.1 Hz, 1H), 2.66 (s,3H).

b)(4-Methoxy-phenyl)-(2-methyl-pyrido[2,3-d]pyrimidin-4-yl)-methyl-amine:To a solution of 2-methyl-pyrido[2,3-d]pyrimidin-4-ol (47 mg, 0.32 mmol)in toluene (2 mL) was added phosphorus oxychloride (0.05 mL, 0.55 mmol)and diisopropylethyl amine (0.12 mL, 0.69 mmol). The solution wasstirred at rt for 25 h, then (4-methoxy-phenyl)-methylamine (45 mg, 0.33mmol) was added. The reaction mixture was stirred at rt for 22 h. Thesolvent was evaporated and the crude was purified by columnchromatography (SiO₂, EtOAc:hexanes/30-100%). The product was collectedas an off-white solid (6 mg, 7%): ¹H NMR (CDCl₃) 8.22 (dd, J=2.1, 4.5Hz, 1H), 7.24 (d, J=2.1 Hz, 1H), 7.15-7.10 (m, 2H), 6.96-6.92 (m, 2H),6.88 (dd, J=4.2, 8.4 Hz, 1H), 3.85 (s, 3H), 3.60 (s, 3H), 2.05 (s, 3H).

EXAMPLE 93

(4-Hydroxy-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine

To a solution of(4-methoxy-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine hydrochloridesalt (106 mg, 0.336 mmol) in dichloromethane (10 mL) at 78° C. was addedslowly boron tribromide (1M in CH₂Cl₂, 0.75 mL) under argon. The coldbath was removed and the reaction mixture was allowed to warm up slowlyto 10° C. in 1.5 h. The reaction mixture was quenched with water (10mL), basified with 2N NaOH to pH=10, and extracted with EtOAc (2×25 mL).The EtOAc extracts were dried and evaporated to give a light brownresidue. The crude was purified by column chromatography (SiO₂,EtOAc:hexanes/15-50%) to give the product as a white solid, which wasfurther purified by recrystallization from MeOH: ^(l)H NMR (acetone-d₆)8.74 (s, 1H), 7.75 (m, 1H), 7.67 (m, 1H), 7.20-7.18 (m, 3H), 7.12 (m,1H), 7.04-6.99 (m, 2H), 3.64 (s, 3H), 2.79 (s, 3H).

EXAMPLE 94

(2-Chloro-quinazolin-4-yl)-(4-ethoxy-phenyl)-amine

The title compound was prepared from 2,4-dichloroquinazoline and4-ethoxyaniline by a procedure similar to example 28 (32%). ¹H NMR(CDCl₃): 7.81 (m, 1H), 7.65 (m, 1H), 7.32 (m, 2H), 7.03 (m, 1H), 6.73(m, 3H), 4.09 (q, J=7.2, 2H), 1.49 (t, J=7.2, 3H).

EXAMPLE 95

(2-Methyl-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl)-amine

The title compound was prepared from 4-chloro-2-methylquinazoline and3-amino-5-methoxypyridine by a procedure similar to example 28 (32%). ¹HNMR (CDCl₃): 8.51 (d, J=1.8, 1H), 8.12 (m, 1H), 7.72-7.89 (m, 3H), 7.49(m, 2H), 6.81 (d, J=8.7, 1H), 3.89 (s, 3H), 2.68 (s, 3H).

EXAMPLE 96

(2-Fluoro-4-methoxy-phenyl)-(2-methyl-quinazolin-4-yl)-amine

The title compound was prepared from 4-chloro-2-methylquinazoline and2-fluoro-4-methoxyaniline by a procedure similar to example 28 (79%). ¹HNMR (CDCl₃): 8.54 (m, 1H), 7.83 (m, 2H), 7.65 (m, 1H), 7.50 (m, 1H),7.47 (s, broad, 1H), 6.74-6.81 (m, 2H), 3.83 (s, 3H), 2.70 (s, 3H).

EXAMPLE 97

(2-Chloro-quinazolin-4-yl)-(4-ethoxy-phenyl)-methylamine

The title compound was prepared from(2-chloro-quinazolin-4-yl)-(4-ethoxy-phenyl)-amine by a proceduresimilar to example 36 (28%). ¹H NMR (CDCl₃): 7.73 (m, 1H), 7.55 (m, 1H),7.12 (m, 2H), 7.00 (m, 1H), 6.93 (m, 3H), 4.07 (q, J=7.2, 2H), 3.61 (s,3H), 1.46 (t, J=7.2, 3H).

EXAMPLE 98

(2-Methyl-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl)-methyl-amine

The title compound was prepared from(2-methyl-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl)-amine by a proceduresimilar to example 36 (28%). ¹H NMR (CDCl₃): 8.03 (d, J=2.7, 1H), 7.77(m, 1H), 7.56 (ddd, J=8.1, 6.3, 1.8, 1H), 7.38 (dd, J=8.7, 3.0, 1H),7.01 (m, 2H), 6.76 (d, J=9.0, 1H), 3.96 (s, 3H), 3.59 (s, 3H), 2.73 (s,3H).

EXAMPLE 99

(2-Fluoro-4-methoxy-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine

The title compound was prepared from(2-methyl-quinazolin-4-yl)-(2-fluoro-4-methoxy-phenyl)-amine by aprocedure similar to example 36 (51%). ¹H NMR (CDCl₃): 7.76 (d, J=8.1,1H), 7.55 (ddd, J=8.1, 6.3, 1.8, 1H), 6.98-7.11 (m, 3H), 6.66-6.76 (m,2H), 3.83 (s, 3H), 3.54 (s, 3H), 2.73 (s, 3H).

EXAMPLE 100

(2-Methyl-quinazolin-4-yl)-(4-nitro-phenyl)-methyl-amine

To a solution of 4-chloro-2-methylquinazoline (1.4 g, 7.84 mmol) and(4-nitro-phenyl)-methylamine (1.09 g, 7.16 mmol) in 20 mL ofdimethylformamide cooled to 0° C. was added sodium hydride (0.6 g, 60oil suspension, 15 mmol). The reaction mixture was stirred at 0° C. for1 h and quenched by adding 200 uL of water. It was diluted with 150 mLof ethyl acetate, washed with water (100 mL×3), saturated NaCl, driedover anhydrous MgSO₄, filtered and concentrated. The residue waspurified by chromatography (30% ethyl acetate/hexanes) to give the titlecompound (1.41 g, 4.78 mmol, 67%). ¹H NMR (CDCl₃): 8.14 (m, 2H), 7.91(m, 1H), 7.71 (ddd, J=8.4, 6.6, 1.8, 1H), 7.19-7.32 (m, 2H), 7.05 (m,2H), 3.76 (s, 3H), 2.82 (s, 3H).

EXAMPLE 101

(4-Amino-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine

A mixture of (2-methyl-quinazolin-4-yl)-(4-nitro-phenyl)-methylamine(200 mg, 0.68 mmol) in 25 mL of ethyl acetate was hydrogenated overPalladium on carbon (70 mg) at 50 psi for 4 h, and the reaction mixturewas filtered through a pad of celite and concentrated. The resultingcrude product was purified by chromatography (50% ethyl acetate/hexane)to obtain the title compound (140 mg, 78%). ¹H NMR (CDCl₃): 7.71 (m,1H), 7.51 (ddd, J=8.4, 6.9, 1.5, 1H), 7.09 (m, 1H), 6.93-7.05 (m, 3H),6.68 (m, 2H), 3.74 (s, broad, 2H), 3.56 (s, 3H), 2.71 (s, 3H).

EXAMPLE 102

(4-Azido-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine

To a solution of (2-methyl-quinazolin-4-yl)-(4-amino-phenyl)-methylamine(20 mg, 0.076 mmol) in 1.2 mL of 1N HCl was added 100 uL of methanol andit was cooled 0° C. One drop of concentrated HCl was added and thesolution was stirred at 0° C. for 0.25 h. To the solution was addeddropwise a solution of sodium nitrite (25 mg, 0.36 mmol) in 200 uL ofwater. The reaction mixture was stirred for 0.5 h, then was added asolution of sodium azide (25 mg, 0.38 mmol) in 300 uL of water followedby another batch of sodium azide (25 mg, 0.38 mmol). The reactionmixture was stirred at the 0° C. for 1 h. The reaction mixture wasdiluted with 50 mL of ethyl acetate, washed with saturated sodiumbicarbonate followed by saturated sodium chloride. The organic layer wasdried over anhydrous Na₂SO₄, filtered and concentrated. The residue waspurified by column chromatography (20-25% ethyl acetate/hexanes) onsilica gel to give the title compound (19.8 mg, 0.068 mmol, 90%). ¹H NMR(CDCl₃): 7.76 (m, 1H), 7.56 (ddd, J=8.1, 6.3, 1.8, 1H), 7.13 (m, 2H),6.98-7.13 (m, 4H), 3.61 (s, 3H), 2.74 (s, 3H).

EXAMPLE 103

(4-Amino-2,6-dibromo-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine andEXAMPLE 104

(4-Amino-2-bromo-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine

To a mixture of (2-methyl-quinazolin-4-yl)-(4-amino-phenyl)-methylamine(53 mg, 0.20 mmol) in 1.8 mL of glacial acetic acid cooled at 12° C. wasadded dropwise a solution of Bromine (64 mg, 0.40 mmol) in 1 mL ofglacial acetic acid. The mixture was stirred for 1 min and the reactionmixture was quenched by adding 1 mL of saturated sodium thiosulfate. Thereaction mixture was diluted with 50 mL of ethyl acetate, and theorganic layer was washed with saturated sodium bicarbonate. The organiclayer was dried over anhydrous MgSO₄, filtered and concentrated. Theresidue was purified by chromatography (25-30% ethyl acetate/hexanes) togive the two compounds.(2-Methyl-quinazolin-4-yl)-(4-amino-2,6-dibromo-phenyl)-methyl-amine(17.5 mg, 0.041 mmol, 21%). ¹H NMR (CDCl₃): 7.78 (m, 1H), 7.58 (ddd,J=8.1, 6.6, 1.2, 1H), 7.24-7.27 (m, 2H), 7.15-7.19 (m, 1H), 7.09 (m,1H), 4.62 (s, broad, 2H), 3.54 (s, 3H), 2.72 (s, 3H) and(2-methyl-quinazolin-4-yl)-(4-amino-2-bromo-phenyl)-methyl-amine. (15mg, 0.045 mmol, 22%). ¹H NMR (CDCl₃): 7.75 (m, 1H), 7.55 (ddd, J=8.4,6.9, 1.5, 1H), 7.31 (d, J=2.7, 1H), 7.13 (m, 1H), 7.03 (ddd, J=8.1, 6.9,1.2, 1H), 6.91 (dd, J=8.1, 2.1, 1H), 6.74 (d, J=8.7, 1H), 4.18 (s,broad, 2H), 3.55 (s, 3H), 2.72 (s, 3H).

EXAMPLE 105

(4-Dimethylamino-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine

To a solution of (2-methyl-quinazolin-4-yl)-(4-amino-phenyl)-methylamine(14 mg, mmol) in 1.5 mL of 37% aqoues formaldehyde solution and 10 uL ofglacial acetic was added Sodium cyanoborohydride (15 mg, 0.24 mmol) andthe mixture was stirred at room temperature for 2 h. The reactionmixture was quenched by adding 50 uL of 1N HCl. It was diluted with 50mL of ethyl acetate, washed with saturated sodium bicarbonate, andfollowed by saturated sodium chloride. The organic layer was dried overanhydrous Na₂SO₄, filtered and concentrated. The residue was purified bycolumn chromatography (25% ethyl acetate/hexanes) on silica gel to givethe title compound (12.4 mg, 0.042 mmol, 80%). ¹H NMR (CDCl₃): 7.71 (m,1H), 7.50 (ddd, J=8.4, 6.9, 1.5, 1H), 7.03-7.09 (m, 3H), 6.95 (ddd,J=8.1, 6.6, 0.9, 1H), 6.70 (m, 2H), 3.57 (s, 3H), 2.99 (s, 6H), 2.71 (s,3H).

EXAMPLE 106

(4-Ethoxy-phenyl)-(2-methyl-quinazolin-4-yl)-amine

The title compound was prepared from 4-chloro-2-methylquinazoline and4-ethoxyaniline by a procedure similar to example 28 (93%). ¹H NMR(CDCl₃): 7.83 (m, 1H), 7.81 (m, 1H), 7.42 (m, 1H), 7.65-7.71 (m, 2H),7.46 (ddd, J=8.4, 6.9, 1.5, 1H), 7.37 (s, broad, 1H), 6.92-6.97 (m, 2H),4.06 (q, J=6.9, 2H), 2.68 (s, 3H), 1.43 (t, J=6.9, 3H).

EXAMPLE 107

(4-Ethoxy-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine

The title compound was prepared from(2-methyl-quinazolin-4-yl)-(4-ethoxy-phenyl)-amine by a proceduresimilar to example 36 (67%). ¹H NMR (CDCl₃): 7.71-7.74 (m, 1H), 7.51(ddd, J=8.1, 6.6, 1.5, 1H), 7.09 (m, 2H), 6.95-7.04 (m, 2H), 6.86-6.92(m, 2H), 4.04 (q, J=6.9, 2H), 3.58 (s, 3H), 2.72 (s, 3H), 1.44 (t,J=6.9, 3H).

EXAMPLE 108

(4-Methoxy-phenyl-2,3,5,6-d₄)-(2-methyl-quinazolin-4-yl)-methyl-amine

a) (4-Methoxy-phenyl-2,3,5,6-d₄)-methylacetamide. To a solution of(4-hydroxy-phenyl-2,3,5,6-d₄)-acetamide (0.410 g, 2.46 mmol) in 15 mL ofdimethylformamide was added methyl iodide (1 mL, 16.1 mmol) and thesolution was cooled to 0° C., then sodium hydride (0.25 g, 60% oilsuspension, 6.3 mmol) was added, and the mixture was stirred for 2 h at0° C. The reaction mixture was quenched by addition of 100 uL of water,and diluted with 100 mL of ethyl acetate. It was washed with water (100mL×3), saturated NaCl, dried over anhydrous MgSO₄, filtered andconcentrated. The residue was purified by chromatography (50% ethylacetate/hexanes) to give the title compound (0.380 g, 1.93 mmol, 78%).¹H NMR (CDCl₃): 3.83 (s, 3H), 3.23 (s, 3H), 1.86 (s, 3H).

b) (4-Methoxy-phenyl-2,3,5,6-d₄)-methylamine. A mixture of(4-methoxy-phenyl-2,3,5,6-d₄)-methylacetamide (280 mg, 1.41 mmol) in 15mL of 2N HCl was refluxed for 4 h. The reaction mixture was cooled to 0°C., basified using cold 2N NaOH and extracted with ethyl acetate (50mL×2). The combined organic extracts were washed with saturated NaCl,dried over anhydrous MgSO₄, filtered and concentrated. The residue waspurified by chromatography (20% ethyl acetate/hexanes) to give the titlecompound (199 mg, 1.28 mmol, 90%). ¹H NMR (CDCl₃): 3.75 (s, 3H), 3.22(s, broad, 1H), 2.80 (s, 3H).

c)(4-Methoxy-phenyl-2,3,5,6-d₄)-(2-methyl-quinazolin-4-yl)-methyl-amine.The title compound was prepared from 4-chloro-2-methylquinazoline and(4-methoxy-phenyl-2,3,5,6-d₄)-methylamine by a procedure similar toexample 28 (65%). ¹H NMR (CDCl₃): 7.73 (m, 1H), 7.52 (ddd, J=8.4, 6.3,1.8, 1H), 6.93-7.03 (m, 2H), 3.84 (s, 3H), 3.59 (s, 3H), 2.71 (s, 3H).

EXAMPLE 109

(4-Methoxy-phenyl)-(2-methyl-6-nitro-quinazolin-4-yl)-methyl-amine

a) 2-Methyl-6-nitro-4H-benzo[d][1,3]oxazin-4-one. A mixture of2-amino-5-nitrobenzoic acid (2.0 g, 10.9 mmol) in 20 mL of aceticanhydride was refluxed for 2 h. The reaction mixture was cooled to roomtemperature and the resulting precipitate was collected and washed withcold diethylether and dried under vacuum to obtain the title compound(1.45 g, 7.01 mmol, 64%). ¹H NMR (CDCl₃): 9.05 (d, J=2.4, 1H), 8.61 (dd,J=9.0, 2.7, 1H), 7.71 (d, J=7.9, 1H), 2.55 (s, 3H).

b) 2-Methyl-6-nitro-quinazoline-4-one. A solution of2-methyl-6-nitro-4H-benzo[d][1,3]oxazin-4-one (200 mg, 0.97 mmol) in asolution of ammonia in dioxane (0.5 M, 2.5 mL, 1.25 mmol) was heated at70° C. for 4 h in a sealed tube. The reaction mixture was cooled to roomtemperature, and the resulting precipitate was collected and washed withcold diethylether and dried. The crude product was used for the nextstep.

c) 4-Chloro-2-methyl-6-nitro-quinazoline. A mixture of2-methyl-6-nitro-quinazoline-4-one (100 mg, 0.49 mmol) anddiisopropylethylamine (250 uL) in 3 mL of toluene was heated to 120° C.for 1 h, then phosphorylchloride (50 uL, 0.54 mmol) was added and themixture was heated at 80° C. for 3 h. The reaction mixture was cooled toroom temperature and poured into ice (about 15 g), basified withsaturated NaHCO₃ and extracted with 75 mL of ethyl acetate. The organiclayer was washed with water (50 mL), 1N citric acid (50 mL), water (50mL) and saturated NaCl, dried over anhydrous Na₂SO₄, filtered andconcentrated. The residue was purified by column chromatography (15%ethyl acetate/hexanes) on silica gel to give the title compound (65.5mg, 0.29 mmol, 60%). ¹H NMR (CDCl₃): 9.17 (d, J=2.4, 1H), 8.69 (dd,J=9.3, 2.4, 1H), 8.13 (d, J=9.3, 1H), 2.93 (s, 3H).

d) (4-Methoxy-phenyl)-(2-methyl-6-nitro-quinazolin-4-yl)-methyl-amine.The title compound was prepared from4-chloro-2-methyl-6-nitro-quinazoline and (4-methoxy-phenyl)-methylamineby a procedure similar to example 28 (87% yield). ¹H NMR (CDCl₃): 8.27(dd, J=9.3, 2.7, 1H), 7.82 (d, J=2.4, 1H), 7.75 (d, J=9.0, 1H), 7.18 (m,2H), 7.01 (m, 1H), 3.88 (s, 3H), 3.65 (s, 3H), 2.73 (s, 3H).

EXAMPLE 110

(6-Amino-2-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine

The title compound was prepared from(4-methoxy-phenyl)-(2-methyl-6-nitro-quinazolin-4-yl)-methyl-amine by aprocedure as described in example 101 (70%). ¹H NMR (CDCl₃): 7.59 (d,J=9.0, 1H), 7.07 (m, 2H), 6.99 (dd, J=8.7, 2.4, 1H), 6.88 (m, 2H), 6.16(d, J=2.1, 1H), 3.48 (s, broad, 2H), 3.82 (s, 3H), 3.55 (s, 3H), 2.68(s, 3H).

EXAMPLE 111

(6-Azido-2-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine

The title compound was prepared from(6-amino-2-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine by aprocedure described for example 102 (83%). ¹H NMR (CDCl₃): 7.69 (d,J=9.0, 1H), 7.10-7.18 (m, 3H), 6.95 (m, 2H), 6.62 (d, J=2.4, 1H), 3.84(s, 3H), 3.59 (s, 3H), 2.70 (s, 3H).

EXAMPLE 112

(4-Methoxy-phenyl)-methyl-(2-methyl-7-nitro-quinazolin-4-yl)-amine

The title compound was prepared from 2-amino-4-nitrobenzoic acid by aprocedure similar to example 109. ¹H NMR (CDCl₃): 8.56 (d, J=2.4, 1H),7.68 (dd, J=9.3, 2.7, 1H), 7.08-7.14 (m, 3H), 6.92-6.97 (m, 2H), 3.86(s, 3H), 3.61 (s, 3H), 2.73 (s, 3H).

EXAMPLE 113

(7-Amino-2-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine

The title compound was prepared from(4-methoxy-phenyl)-(2-methyl-7-nitro-quinazolin-4-yl)-methyl-amine by aprocedure as described in example 101. ¹H NMR (CDCl₃/d₄-methanol):7.11-7.15 (m, 2H), 6.93-6.96 (m, 2H), 6.86 (m, 1H), 6.63 (d, J=9.3, 1H),6.35 (dd, J=9.3, 2.4, 1H), 3.86 (s, 3H), 3.60 (s, 3H), 2.65 (s, 3H).

EXAMPLE 114

(7-Azido-2-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine

The title compound was prepared from(7-amino-2-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine by aprocedure as described for example 102. ¹H NMR (CDCl₃): 7.36 (d, J=2.4,1H), 7.08-7.13 (m, 2H), 6.88-6.96 (m, 3H), 6.59 (dd, J=9.0, 2.4, 1H),3.84 (s, 3H), 3.57 (s, 3H), 2.69 (s, 3H).

EXAMPLE 115

(3,5-Dibromo-4-methoxy-phenyl)-(2-methyl-6-nitro-quinazolin-4-yl)-methyl-amine

a) N-(3,5-dibromo-4-hydroxyphenyl)acetamide: To a solution ofN-(4-hydroxyphenyl)acetamide (0.50 g, 3.03 mmol) in glacial acetic acid(1 mL), methanol (1 mL) and methylene chloride (5 mL) cooled at 0° C.was added a solution of bromine (1 g, 6.25 mmol) in 1 mL of glacialacetic acid, and the mixtute was stirred at 0° C. for 2 h. Additionalbromine (1 g, 6.25 mmol) in 1 mL of glacial acetic acid was added andthe mixture was stirred for 0.75 h at 0° C. The reaction mixture wasdiluted with 100 mL of ethyl acetate, washed with 1M Na₂SO₃ (100 mL),water, half saturated NaHCO₃ (100 mL) and saturated NaCl (100 mL). Theorganic layer was dried over Na₂SO₄, filtered and concentrated. Thecrude product was purified by column chromatography (40-45% ethylacetate/hexanes) on silica gel to give the title compound (0.52 g, 1.61mmol, 53%). ¹H NMR (CDCl₃): 9.96 (s, broad, 1H), 9.64 (s, broad, 1H),7.77 (s, 2H), 2.01 (s, 3H).

b) N-(3,5-dibromo-4-methoxyphenyl)-N-methylacetamide: The title compoundwas prepared from N-(3,5-dibromo-4-hydroxyphenyl)acetamide (510 mg, 1.58mmol) by a procedure similar to Example 108a (460 mg, 1.36 mmol, 86%).¹H NMR (CDCl₃): 7.39 (s, 2H), 3.92 (s, 3H), 3.22 (s, 3H), 1.92 (s, 3H).

c) (3,5-dibromo-4-methoxy-phenyl)-methylamine: The title compound wasprepared from N-(3,5-dibromo-4-methoxyphenyl)-N-methylacetamide (426 mg,1.26 mmol) by a procedure similar to Example 108b (323 mg, 1.09 mmol,87%). ¹H NMR (CDCl₃): 6.72 (s, 2H), 3.80 (s, 3H), 3.67 (s, broad, 1H),2.78 (d, J=5.1, 3H).

d)(3,5-Dibromo-4-methoxy-phenyl)-(2-methyl-6-nitro-quinazolin-4-yl)-methyl-amine.The title compound was prepared from4-chloro-2-methyl-5-nitroquinazoline and(3,5-dibromo-4-methoxy-phenyl)-methylamine by a procedure similar toexample 28 (61% yield). ¹H NMR (CDCl₃): 8.35 (dd, J=9.3, 2.4, 1H), 7.86(d, J=2.1, 1H), 7.84 (d, J=9.0, 1H), 7.47 (m, 1H), 7.44 (s, 2H), 3.98(s, 3H), 3.66 (s, 3H), 2.75 (s, 3H).

EXAMPLE 116

4-(N-Methyl-N-(2-methylquinazolin-4-yl)amino)benzoic Acid

The title compound was prepared from 4-chloro-2-methylquinazoline and4-(methylamino)benzoic acid by a procedure described for example lb. ¹HNMR (CDCl₃): 8.42-8.39 (m, 1H), 8.28 (m, 2H), 7.84 (m, 1H), 7.45 (m,2H), 7.37 (m, 1H), 7.22 (m, 1H), 6.84 (d, J=1H, 8.4), 3.91 (s, 3H), 3.01(s, 3H).

EXAMPLE 117

Ethyl 4-(N-(4-Methoxy-phenyl)-N-methylamino)quinazoline-2-carboxylate

The title compound was prepared from ethyl4-chloroquinazoline-2-carboxylate and (4-methoxy-phenyl)-methylamine byusing the procedure described for example 1b. ¹H NMR (CDCl₃): 7.98-8.02(m, 1H), 7.61 (ddd, J=1H, 8.1, 6.9, 1.5), 7.08-7.17 (m, 3H), 7.01-7.05(m, 1H), 6.91-6.96 (m, 2H), 4.56 (q, J=2H, 7.2), 3.84 (s, 3H), 3.71 (s,3H), 1.50 (t, J=2H, 7.2).

EXAMPLE 118

4-(N-(4-Methoxy-phenyl)-N-methylamino)quinazoline-2-carboxylic Acid

A mixture of ethyl4-(N-(4-methoxy-phenyl)-N-methylamino)quinazoline-2-carboxylate (560 mg,1.66 mmol) and sodium hydroxide (126 mg, 3.15 mmol) in 25 mL of methanoland water (1:3) was stirred at room temperature for 5 h. The solventswere removed under vaccum, and the residue was dissolved in 50 mL ofwater and acidified to pH 3. The white precipitate was collected andwashed with water and dried (380 mg, 1.23 mmol, 74%). ¹H NMR (CDCl₃):8.02-8.05 (m, 1H), 7.68 (ddd, J=1H, 8.4, 6.9, 1.5), 7.14-7.20 (m, 3H),7.02-7.05 (m, 1H), 6.94-6.99 (m, 2H), 3.87 (s, 3H), 3.74 (s, 3H).

EXAMPLE 119

Succinimidyl 4-(N-Methyl-N-(2-methylquinazolin-4-yl)amino)benzoic AcidEster

A solution of 4-(N-methyl-N-(2-methylquinazolin-4-yl)amino)benzoic acid(250 mg, 0.852 mmol), N-hydroxysuccinimide (75 mg, 0.653 mmol) anddicyclohexylcarbodiimide (135 mg, 0.653 mmol) in 50 mL of methylenechloride was refluxed overnight. The reaction mixture was cooled to roomtemperature and diluted with 100 mL of ethyl acetate, washed with water(3×100 mL), saturated NaCl and the organic layer was dried over Na₂SO₄,filtered and concentrated. The crude product was purified bychromatography (75% ethyl acetate/hexanes) on silica gel to give thetitle compound (170 mg, 0.435 mmol, 51%). ¹H NMR (CDCl₃): 8.06 (m, 2H),7.95 (m, 1H), 7.71 (m, 1H), 7.11-7.22 (m, 4H), 3.76 (s, 3H), 2.84 (s,3H), 2.81-2.92 (m, 4H).

EXAMPLE 120

(2-Methylthio-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine

A mixture of (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine(150 mg, 0.5 mmol), sodium methanethiolate (105 mg, 1.5 mmol) in 5 mL ofsolvent (THF:MeOH:water=3:1:1) was stirred at 70° C. for 4 h. Thereaction mixture was diluted with 30 mL of ethyl acetate and it waswashed with brine, dried over anhydrous Na₂SO₄, filtered andconcentrated. The crude product was purified by chromatography on silicagel with acetate and hexane (1:5) as eluent, yielding 11 mg of titlecompound (7%). ¹H NMR (CDCl₃): 7.65 (d, J=8.4 Hz, 1H), 7.51-7.45 (m,1H), 7.14-7.10 (m, 2H), 6.93-6.89 (m, 4H), 3.84 (s, 3H), 3.58 (s, 3H),2.67 (s, 3H).

EXAMPLE 121

(2-Azido-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine

The title compound was prepared from(2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (150 mg, 0.5mmol), sodium azide (97.5 mg, 1.5 mmol) in 5 mL of solvent(THF:MeOH:water=3:1:1) by a procedure similar to that of example 120(4%). ¹H NMR (CDCl₃): 8.45 (d, J=8.4 Hz, 1H), 7.78-7.72 (m, 1H),7.27-7.22 (m, 2H), 7.19-7.14 (m, 2H), 6.95 (d, J=8.7 Hz, 2H), 3.86 (s,3H), 3.69 (s, 3H).

EXAMPLE 122

(2-Dimethylamino-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine

A mixture of (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine(150 mg, 0.5 mmol), 2.0 M dimethylamine in methanol (2.0 ml, 4 mmol) ina sealed tube was stirred at 70-80° C. overnight. The mixture was filledand the filtration was concentrated by vacuum. The residue was extractedwith ethyl acetate and was washed with brine, dried over anhydrousNa₂SO₄, filtered and concentrated. The crude product was purified bychromatography on silica gel with acetate and hexane (1:9) as eluent,yielding 128 mg of title compound (83%). ¹H NMR (CDCl₃): 7.44 (d, J=7.8Hz, 1H), 7.36-7.30 (m, 1H), 7.11-7.08 (m, 2H), 6.90-6.85 (m, 3H),6.65-6.59 (m, 1H), 3.82 (s, 3H), 3.51 (s, 3H), 3.30 (s, 6H).

EXAMPLE 123

(2-Methylamino-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine

The title compound was prepared from(2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (150 mg, 0.5mmol), 2.0 M methylamine in THF (2.0 ml, 4 mmol) by a procedure similarto that of example 122 (53.7%). ¹H NMR (CDCl₃): 7.45 (d, J=7.8 Hz, 1H),7.39-7.33 (m, 1H), 7.11-7.07 (m, 2H), 6.90-6.87 (m, 3H), 6.69-6.64 (m,1H), 4.95 (brs, 1H), 3.82 (s, 3H), 3.50 (s, 3H), 3.11 (d, J=5.1 Hz, 3H).

EXAMPLE 124

(4-Fluoro-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine

The title compound was prepared from 4-chloro-2-methyl-quinazoline(178.6 mg, 1.0 mmol) and (4-fluoro-phenyl)-methyl-amine (125 mg, 2.52mmol) by a procedure similar to example 28 (46.8%). ¹H NMR (CDCl₃): 7.76(dd, J=0.9 Hz, J=8.3 Hz, 1H), 7.58-7.52 (m,1H), 7.16-7.00 (m, 6H), 3.60(s, 3H), 2.73 (s, 3H),

EXAMPLE 125

(6-Methoxy-pyridazin-3-yl)-(2-methyl-quinazolin-4-yl)-methyl-amine

a) 3-Amino-6-methoxy-pyridazine: A mixture of3-amino-6-chloro-pyridazine (500 mg, 3.86 mmol), sodium methoxide (1.0ml, 4.4 mmol, 25% w/w) and copper powder (331 mg, 5.17 mmol) in methanol(3 ml) was heated in a sealed tube at 160° C. for 24 h. After cooling,the reaction mixture was diluted with methanol (10 ml) and filtered, andthe filtrate was concentrated by vacuum. The residue was purified bychromatography on silica gel with acetate and hexane (1:2) as eluent,yielding 413 mg of title compound (85.7%). ¹H NMR (CDCl₃): 6.81 (m, 2H),4.62 (brs, 2H), 4.00 (s, 3H).

b) (6-Methoxy-pyridazin-3-yl)-methyl-amine: To a solution of3-amino-6-methoxy-pyridazine (90 mg, 0.72 mmol) in THF (2 ml) at 0° C.was added sodium hydride (44 mg, 1.08 mmol, 60% oil dispersion),followed by methyl iodide (0.07 ml, 1.08 mmol). The mixture was stirredat 0° C. for 1 h, then allowed to warm to room temperature and stirredfor another 2 h. The reaction mixture was diluted with EtOAc (10 ml),washed with saturated NaHCO₃ aq., brine, dried over Na₂SO₄, filtered andconcentrated by vacuum. The residue was purified by chromatography onsilica gel with acetate and hexane (1:2 to 1:1) as eluent, yielding 6.0mg of title compound (6.0%). ¹H NMR (CDCl₃): 6.79 (d, J=9.0 Hz, 1H),6.68 (d, J=10.5 Hz, 1H), 4.29 (brs, 1H), 4.01 (s, 3H), 3.01 (d, J=4.8Hz, 3H).

c) (6-Methoxy-pyridazin-3-yl)-(2-methyl-quinazolin-4-yl)-methyl-amine:To a solution of (6-methoxy-pyridazin-3-yl)-methyl-amine (10 mg, 0.072mmol) in DMF (1 ml) at 0° C. was added sodium hydride (4.3 mg, 0.11mmol, 60% oil dispersion), followed by 4-chloro-2-methyl-quinazoline(12.9 mg, 0.072 mmol). The mixture was stirred at 0° C. for 1 h, thenallowed to warm to room temperature and stirred for another 2 h. Thereaction mixture was diluted with EtOAc (10 ml), washed with saturatedNaHCO₃ aq., brine, dried over Na₂SO₄, filtered and concentrated byvacuum. The residue was purified by chromatography on silica gel withacetate and hexane (1:2 to 1:1) as eluent, yielding 2.0 mg of titlecompound (10%). ¹H NMR (CDCl₃): 7.90 (d, J=8.1 Hz, 1H), 7.73 (t, J=8.4Hz, 1H), 7.48 (d, J=8.7 Hz, 1H), 7.34-7.31 (m, 1H), 6.94 (d, J=9.3 Hz,1H), 6.81 (d, J=9.6 Hz, 1H), 4.12 (s, 3H), 3.85 (s, 3H), 2.78 (s, 3H).

EXAMPLE 126

(5-Methoxy-pyrazin-2-yl)-(2-methyl-quinazolin-4-yl)-methyl-amine

a) 2-Amino-5-methoxy-pyrazine: The title compound was prepared from2-amino-5-bromo-pyrazine (500 mg, 2.87 mmol) and sodium methoxide (1.0ml, 4.4 mmol, 25% w/w) by a procedure similar to example 125a (29%). ¹HNMR (CDCl₃): 7.76 (s, 1H), 7.56 (s, 1H), 4.20 (brs, 2H), 3.88 (s, 3H).

b) (5-Methoxy-pyrazin-2-yl)-(2-methyl-quinazolin-4-yl)-amine: The titlecompound was prepared from 2-amino-5-methoxy-pyrazine (105 mg, 0.84mmol) and 4-chloro-2-methyl-quinazoline (150 mg, 0.84 mmol) by aprocedure similar to example 125c, yielding 106 mg of the title product.

c) (5-Methoxy-pyrazin-2-yl)-(2-methyl-quinazolin-4-yl)-methyl-amine: Thetitle compound was prepared from(5-methoxy-pyrazin-2-yl)-(2-methyl-quinazolin-4-yl)-amine (106 mg, 0.40mmol) by a procedure similar to example 36 (56%). ¹H NMR (CDCl₃): 8.06(d, J=1.2 Hz, 1H), 7.85-7.81 (m, 1H), 7.74 (d, J=1.5 Hz, 1H), 7.65-7.60(m, 1H), 7.17-7.05 (m, 2H), 3.94 (s, 3H), 3.70 (s, 3H), 2.78 (s, 3H).

EXAMPLE 127

(4-hydroxy-phenyl)-(2-methyl-quinazolin-4-yl)-amine

The title compound was prepared from 4-chloro-2-methyl-quinazoline (818mg, 4.58 mmol), 4-hydroxy-aniline (500 mg, 4.58 mmol) by a proceduresimilar to example 1b to give 498 mg (43%) of off white solids. ¹H NMR(DMSO-d₆): 9.51 (s, 1H), 9.34 (s, 1H), 8.44 (d, J=7.8 Hz, 1H), 7.77 (t,J=8.4 Hz, 1H), 7.67-7.48 (m, 4H), 6.79 (d, J=7.8 Hz, 2H), 2.45 (s, 3H).

EXAMPLE 128

(2-Dimethylamino-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl)-methyl-amine

The title compound was prepared from(2-chloro-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl)-methyl-amine (69 mg,0.23 mmol) and 2.0 M dimethylamine in methanol (4 ml, 8 mmol) by aprocedure similar to example 122 (51%). ¹H NMR (CDCl₃): 8.02 (d, J=2.7Hz, 1H), 7.47 (d, J=8.1 Hz, 1H), 7.38-7.34 (m, 2H), 6.93 (d, J=8.4 Hz,1H), 6.75-6.66 (m, 2H), 3.94 (s, 3H), 3.51 (s, 3H), 3.30 (s, 6H).

EXAMPLE 129

(2-Methylamino-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl)-methyl-amine

The title compound was prepared from(2-chloro-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl)-methyl-amine (69 mg,0.23 mmol) and 2.0 M methylamine in THF (4 ml, 8 mmol) by a proceduresimilar to example 122 to give 20 mg (30%) of yellow solids. ¹H NMR(CDCl₃): 8.02-8.01 (m, 1H), 7.48 (d, J=8.1 Hz, 1H), 7.42-7.34 (m, 2H),6.97-6.94 (m, 1H), 6.76-6.70 (m, 2H), 5.01 (brs, 1H), 3.95 (s, 3H), 3.50(s, 3H), 3.12 (d, J=5.1 Hz, 3H).

EXAMPLE 130 AND 131

(2-Chloro-quinazolin-4-yl)-(cis-4-methylcyclohexyl)-amine and(2-chloro-quinazolin-4-yl)-(trans-4-methylcyclohexyl)-amine

The title compounds were prepared from 2,4-dichloro-quinazoline and4-methylcyclohexyl-amine by a procedure similar to example 28. Theisomers were separated by chromatography (10-12% ethyl acetate/haxane).(2-Chloro-quinazolin-4-yl)-(cis-4-methylcyclohexyl)-amine. ¹H NMR(CDCl₃): 7.66-7.79 (m, 3H), 7.46 (ddd, J=1.8, 6.3, 8.4, 1H), 5.96 (d,broad, J=6.6, 1H), 4.49 (m, 1H), 1.68-1.87 (m, 7H), 1.25 (m, 2H), 0.99(d, J=6.6, 3H).(2-Chloro-quinazolin-4-yl)-(trans-4-methylcyclohexyl)-amine. ¹H NMR(CDCl₃): 7.67-7.78 (m, 3H), 7.43 (ddd, J=1.8, 6.6, 8.4, 1H), 5.78 (d,broad, J=7.5, 1H), 4.22 (m, 1H), 2.15-2.21 (m, 2H), 1.76-1.82 (m, 2H),1.11-1.46 (m, 5H), 0.94 (d, J=6.6, 3H).

EXAMPLE 132

(2-Chloro-quinazolin-4-yl)-(cis-4-methylcyclohexyl)-methyl-amine

The title compound was prepared from(2-chloro-quinazolin-4-yl)-(cis-4-methylcyclohexyl)-amine by a proceduresimilar to example 36. ¹H NMR (CDCl₃): 7.88 (m, 1H), 7.75-7.78 (m, 1H),7.68 (ddd, J=1.5, 6.9, 8.4, 1H), 7.37 (ddd, J=1.5, 6.9, 8.4, 1H), 4.36(m, 1H), 3.24 (s, 3H), 1.86-2.00 (m, 3H), 1.61-1.75 (m, 6H), 1.05 (d,J=7.2, 3H).

EXAMPLE 133

(2-Chloro-quinazolin-4-yl)-(trans-4-methylcyclohexyl)-methyl-amine

The title compound was prepared from(2-chloro-quinazolin-4-yl)-(trans-4-methylcyclohexyl)-amine by aprocedure similar to example 36. ¹H NMR (CDCl₃): 7.89 (m, 1H), 7.74-7.78(m, 1H), 7.68 (ddd, 0.9, 6.6, 8.1, 1H), 7.37 (ddd, J=1.2, 6.6, 8.1, 1H),4.38 (m, 1H), 3.21 (s, 3H), 1.67-1.95 (m, 6H), 1.39 (m, 1H), 1.4-1.25(m, 2H), 0.93 (d, J=6.3, 3H).

EXAMPLE 134

(2-Methyl-quinazolin-4-yl)-(pyrazin-2-yl)-methyl-amine

The title compound was prepared from 4-chloro-2-methyl-quinazoline and2-amino-pyrazine in two steps by a procedure similar to examples 100 and36. ¹H NMR (CDCl₃): 8.27 (dd, J=1.5, 2.4, 1H), 8.13-8.14 (m, 2H), 7.95(d, J=8.4, 1H), 7.77 (ddd, J=1.5, 6.6, 8.4, 1H), 7.45-7.48 (m, 1H), 7.34(ddd, J=0.9, 6.6, 8.1, 1H), 3.78 (s, 3H), 2.83 (s, 3H).

EXAMPLE 135

(2-Methyl-quinazolin-4-yl)-(pyridin-4-yl)-amine

The title compound was prepared from 4-chloro-2-methyl-quinazoline and4-amino-pyridine by a procedure similar to examples 100. ¹H NMR (CDCl₃):8.58 (m, 1H), 7.79-7.93 (m, 5H), 7.70 (s, broad, 1H), 7.55 (ddd, J=1.2,6.9, 8.1, 1H), 2.79 (s, 3H).

EXAMPLE 136

(2-Methyl-quinazolin-4-yl)-(pyridin-4-yl)-methyl-amine

The title compound was prepared from 4-chloro-2-methyl-quinazoline(0.178 g, 2.13 mmol) and (pyridin-4-yl)-methyl-amine (0.108 g, 1.84mmol) by a procedure similar to examples 125c (0.224 g, 49%). ¹H NMR(CDCl₃): 8.39 (m, 2H), 7.91 (d, J=8.4, 1H), 7.73 (ddd, J=1.2, 6.6, 8.4,1H), 7.41 (m, 1H), 7.23-7.29 (m, 1H), 6.79-6.82 (m, 2H), 3.70 (s, 3H),2.83 (s, 3H).

EXAMPLE 137

(5-Methoxy-pyridin-2-yl)-(2-methyl-quinazolin-4-yl)-amine

a) 2-Amino-5-methoxy-pyridine. A mixture of 2-amino-5-iodo-pyridine (1g, 4.54 mmol) in 20 mL of absolute methanol with 400 mg of copper powderand sodium methoxide (6 mmol) was heated at 160° C. overnight in a sealtube. The reaction mixture was cooled to room temperature, diluted with80 mL of methanol and filtered through a pad of celite. The filtrate wasconcentrated and the residue was purified by chromatography (80% ethylacetate/hexane) to give the title compound (174 mg, 31%). ¹H NMR(CDCl₃): 7.78 (d, J=2.7, 1H), 7.09 (dd, J=3.0, 9.0, 1H), 6.48 (d, J=9.0,1H), 3.78 (s, 3H).

b) (5-Methoxy-pyridin-2-yl)-(2-methyl-quinazolin-4-yl)-amine: The titlecompound was prepared from 4-chloro-2-methyl-quinazoline and2-amino-5-methoxy-pyridine by a procedure similar to example 28.

EXAMPLE 138

(5-Methoxy-pyridin-2-yl)-(2-methyl-quinazolin-4-yl)-methyl-amine

The title compound was prepared from(5-methoxy-pyridin-2-yl)-(2-methyl-quinazolin-4-yl)-amine by a proceduresimilar to example 36. ¹H NMR (CDCl₃): 8.31 (d, 3.3, 1H), 7.80 (d,J=8.4, 1H), 7.58 (ddd, J=1.5, 6.6, 8.4, 1H), 7.13 (dd, J=3.3, 9.0, 1H),6.99-7.10 (m, 2H), 6.82 (d, J=9.0, 1H), 3.87 (s, 3H), 3.70 (s, 3H), 2.76(s, 3H).

EXAMPLE 139

Difluoromethyl-(4-methoxy-phenyl)-(2-methyl-quinazolin-4-yl)-amine

A solution of (4-methoxy-phenyl)-(2-methyl-quinazolin-4-yl)-amine (100mg, 0.35 mmol) in 3 mL of dimethylformamide in a 15 mL high pressurereaction vessel was cooled to −78° C. Diflurochloromethane (about 0.8mL) was condensed into the solution, then cesium carbonate (160 mg, 0.49mmol) was added. The reaction vessel was capped and heated at 80° C.overnight. The reaction mixture was cooled to room temperature andcooled to 78° C. and the seal tube was uncapped, warm to roomtemperature and allowed to stand for 2 h. The reaction mixture wasdiluted with 50 mL of ethyl acetate and the organic layer was washedwith water (50 mL×3), followed by saturated aqueous NaCl. The organiclayer was dried over anhydrous sodium sulfate, filtered andconcentrated. The residue was purified by chromatography (30% ethylacetate/hexane, 6 drops triethylamine/500 mL of solvent) to give thetitle compound (35 mg, 0.111 mmol, 32%). ¹H NMR (CDCl₃): 8.35 (dd,J=1.8, 8.1, 1H), 7.35 (m, 3H), 7.25 (t, J=72.1, 1H), 7.21-7.25 (m, 2H),6.86-6.91 (m, 2H), 3.82 (s, 3H), 2.48 (s, 3H).

EXAMPLE 140

(4-Methoxy-phenyl)-(2-methyl-pteridin-4-yl)-methyl-amine

a) 4-Chloro-2-methyl-pteridine. A mixture of6-chloro-2-methyl-pyrimidine-4,5-diamine (37 mg, 0.233 mmol) and1,4-dioxane-2,3-diol (32 mg, 0.266 mmol) in 0.8 mL of absolute ethanolwas stirred at room temperature for 2 h. The reaction mixture wasevaporated to dryness and the residue was purified by columnchromatography (50% ethyl acetate/hexane) to give the title compound (41mg, 0.227 mmol, 97%). ¹H NMR (CDCl₃): 9.24 (d, J=1.8, 1H), 9.05 (d,J=1.5, 1H), 2.99 (s, 3H).

b) (4-Methoxy-phenyl)-(2-methyl-pteridin-4-yl)-methyl-amine. The titlecompound was prepared from 4-chloro-2-methyl-pteridine and(4-methoxy-phenyl)-methyl-amine by a procedure similar to example 28(67%). ¹H NMR (CDCl₃): 8.73 (d, J=1.8, 1H), 8.22 (d, J=1.8, 1H),7.07-7.10 (m, 2H), 6.86-6.92 (m, 2H), 3.85 (s, 3H), 3.69 (s, 3H), 2.73(s, 3H).

EXAMPLE 141

(5-Methoxy-pyrimidin-2-yl)-(2-methyl-quinazolin-4-yl)-amine

a) 2-Amino-5-methoxy-pyrimidine: The title compound was prepared from2-amino-5-iodo-pyrimidine (2.0 g, 9.0 mmol) and sodium methoxide (10 ml,44 mmol, 25% w/w) by a procedure similar to example 125a (21%). ¹H NMR(CDCl₃): 8.05 (s, 2H), 4.78 (brs, 2H), 3.81 (s, 3H).

b) (5-Methoxy-pyrimidin-2-yl)-(2-methyl-quinazolin-4-yl)-amine: Thetitle compound was prepared from 2-amino-5-methoxy-pyrimidine (240 mg,1.92 mmol) and 4-chloro-2-methyl-quinazoline (343 mg, 1.92 mmol) by aprocedure similar to example 125c, yielding 283 mg of the title product(55%). ¹H NMR (CDCl₃): 8.69 (dd, J=1.5 Hz, J=8.1 Hz, 1H), 8.43 (s, 2H),7.73-7.67 (m, 1H), 7.60 (d, J=7.2 Hz, 1H), 7.49-7.43 (m, 1H), 3.95 (s,3H), 2.58 (s, 3H).

EXAMPLE 142

(5-Methoxy-pyrimidin-2-yl)-(2-methyl-quinazolin-4-yl)-methyl-amine

The title compound was prepared from(5-methoxy-pyrimidin-2-yl)-(2-methyl-quinazolin-4-yl)-amine (170 mg,0.64 mmol) by a procedure similar to example 36 (50%). ¹H NMR (CDCl₃):8.12 (s, 2H), 7.91 (d, J=8.4 Hz, 1H), 7.74-7.69 (m, 1H), 7.38-7.34 (m,1H), 7.30-7.24 (m, 1H), 3.85 (s, 3H), 3.78 (s, 3H), 2.83 (s, 3H).

EXAMPLE 143 Identification of(2-Chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine and Analogsas Caspase Cascade Activators and Inducers of Apoptosis in Solid TumorCells

Human breast cancer cell lines T-47D and DLD-1 were grown according tomedia component mixtures designated by American Type Culture Collection+10% FCS (Invitrogen Corporation), in a 5% CO₂-95% humidity incubator at37° C. T-47D and DLD-1 cells were maintained at a cell density between50 and 80% confluency at a cell density of 0.1 to 0.6×10⁶ cells/mL.Cells were harvested at 600×g and resuspended at 0.65×10⁶ cells/mL intoappropriate media +10% FCS. An aliquot of 22.5 μL of cells was added toa well of a 384-well microtiter plate containing 2.5 μL of a 10% DMSO inRPMI-1640 media solution containing 0.16 to 100 μM of(2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine or other testcompound (0.016 to 10 μM final). An aliquot of 22.5 μL of cells wasadded to a well of a 384-well microtiter plate containing 2.5 μL of a10% DMSO in RPMI-1640 media solution without test compound as thecontrol sample. The samples were mixed by agitation and then incubatedat 37° C. for 48 h in a 5% CO₂-95% humidity incubator. After incubation,the samples were removed from the incubator and 25 μL of a solutioncontaining 14 μM of N-(Ac-DEVD)-N′-ethoxycarbonyl-R110 fluorogenicsubstrate (Cytovia, Inc.; WO99/18856), 20% sucrose (Sigma), 20 mM DTT(Sigma), 200 mM NaCl (Sigma), 40 mM Na PIPES buffer pH 7.2 (Sigma), and500 μg/mL lysolecithin (Calbiochem) was added. The samples were mixed byagitation and incubated at room temperature. Using a fluorescent platereader (Model SPECTRAfluor Plus, Tecan), an initial reading (T=0) wasmade approximately 1-2 min after addition of the substrate solution,employing excitation at 485 nm and emission at 530 nm, to determine thebackground fluorescence of the control sample. After the 3 h incubation,the samples were read for fluorescence as above (T=3 h).

Calculation:

The Relative Fluorescence Unit values (RFU) were used to calculate thesample readings as follows:

RFU_((T=3h))−Control RFU_((T=0))=Net RFU_((T=3h))

The activity of caspase cascade activation was determined by the ratioof the net RFU value for(2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine or other testcompounds to that of control samples. The EC₅₀ (nM) was determined by asigmoidal dose-response calculation (Prism 3.0, GraphPad Software Inc.).

The caspase activity (Ratio) and potency (EC₅₀) are summarized in TableI:

TABLE I Caspase Activity and Potency Exa. T-47D (24 hr) T-47D (48 hr)Cmpd. Ratio EC₅₀ (nM) Ratio EC₅₀ (nM) 1 8.7 2 NA NA 2 6.7 31 NA NA 3 8.179 NA NA 4 7.1 872 NA NA 5 10.3 24 NA NA 6 6.7 219 NA NA 7 1.2 >100001.0 >10000 8 1.0 >10000 NA NA 9 NA NA 1.8 >10000 10 NA NA 12.8 48 11 9.08 12.5 10 12 5.3 8 12.8 9 13 8.9 260 NA NA 14 9.7 1345 12.3 1326 15 5.756 11.5 89 16 7.6 296 NA NA 17 3.0 7945 NA NA 18 1.0 >10000 1.0 >1000019 1.0 >10000 1.0 >10000 20 13.1 161 NA NA 21 1.0 >10000 1.0 >10000 221.0 >10000 1.0 >10000 23 1.0 >10000 1.0 >10000 24 1.0 >10000 2.4 9460 25NA NA 5.8 42 26 NA NA 15.7 178 27 NA NA 1.0 >10000 28 1.0 >100001.0 >10000 29 NA NA 1.0 >10000 30 NA NA 1.0 >10000 31 8.0 317 14.7 56332 NA NA 1.0 >10000 33 NA NA 1.0 >10000 34 7.5 7 NA NA 35 7.2 141 NA NA36 6.7 6 NA NA 37 3.3 2693 NA NA 38 3.4 2933 NA NA 39 4.5 693 NA NA 40NA NA 6.1 47 41 NA NA 12.4 20 42 8.6 282 14.6 265 43 NA NA 14.7 34 44 NANA 14.3 501 45 NA NA 1.0 >10000 46 12.8 2184 9.4 2272 47 NA NA 11.5 18748 NA NA 12.5 137 49 7.5 29 13.4 22 50 NA NA 1.0 >10000 51 NA NA0.9 >10000 52 NA NA 10.8 6 53 8.3 5 11.4 11 54 NA NA 12.5 46 55 NA NA9.0 1 56 NA NA 4.9 5 57 NA NA 6.2 432 58 NA NA 10.8 1 59 NA NA 7.1 11 60NA NA 6.5 13 61 NA NA 9.2 4046 62 NA NA 12.7 316 63 NA NA 10.9 427 64 NANA 1 >10000 65 NA NA 13.7 599 66 7.2 18 12.5 22 67 NA NA 12.5 38 68 NANA 13.1 4 69 NA NA 1 >1000 70 NA NA 11.3 42 71 NA NA 6.9 2265 72 9.0 27.4 2 73 6.2 679 5.7 543 74 6.6 15 5.3 36 75 1.5 >10000 NA NA 76 5.6 714.1 8 77 5.7 700 12.3 2107 78 0.6 >10000 NA NA 79 0.7 >10000 NA NA 808.3 5752 NA NA 81 1.9 >10000 NA NA 82 1.0 >10000 NA NA 83 NA NA 10.8 16884 6.7 8 NA NA 85 7.6 2 NA NA 86 6.2 41 NA NA 87 6.3 25 NA NA 88 7.6 556NA NA 89 NA NA 7.8 24 90 10.6 2 NA NA 91 8.3 4 NA NA 92 10.1 16 NA NA 9311.3 65 NA NA 94 NA NA 1.0 >10000 95 1.0 >10000 NA NA 96 1.0 >10000 NANA 97 NA NA 9.0 5 98 5.4 14 12.9 8 99 6.9 4 NA NA 100 8.9 474 NA NA 1019.5 175 NA NA 102 8.8 5 11.3 16 103 9.3 552 NA NA 104 8.6 134 NA NA 1058.5 2 NA NA 106 1.1 >10000 NA NA 107 5.2 5 NA NA 108 4.8 1 NA NA 109 4.6274 NA NA 110 8.8 7 NA NA 111 9.4 32 NA NA 112 1.0 >10000 NA NA 113 3.7735 NA NA 114 7.2 130 NA NA 115 1.0 >10000 NA NA 116 1.0 >10000 NA NA117 7.4 134 NA NA 118 1.0 >10000 NA NA 119 11.8 4288 NA NA 120 5.2 8 NANA 121 8.8 30 NA NA 122 8.2 16 NA NA 123 8.2 8 NA NA 124 5.2 408 NA NA125 8.3 385 NA NA 126 7.6 55 NA NA 127 1.2 >10000 NA NA 128 10 58 NA NA129 10 27 NA NA 130 1.2 >10000 NA NA 131 1.2 >10000 NA NA 132 1.2 >10000NA NA 133 1.2 >10000 NA NA 134 1.2 >10000 NA NA 135 1.2 >10000 NA NA 1361.2 >10000 NA NA 137 1.2 >10000 NA NA 138 5.0 15 NA NA 139 5.6 4662 NANA 140 7.0 27 NA NA 141 1.2 >10000 NA NA 142 7.5 141 NA NA NA = Notavailable

The following substituted N′-methyl-N′-(quinazolin-4-yl)benzohydrazidesand analogs also are identified as potent caspase cascade activators andinducers of apoptosis and are thus useful in treating the variousdiseases and disorders discussed above.

T-47D (24 hr) T-47D (48 hr) Compound Ratio EC₅₀ (nM) Ratio EC₅₀ (nM)

  4-chloro-N′-methyl-N′-(2- (methylthio)quinazolin-4- yl)benzohydrazideNA NA 14.4 138

  N′-methyl-N′-(2- (methylthio)quinazolin-4- yl)thiophene-2-carbohydrazide NA NA 10.1 737

  N′-methyl-N′-(2- (methylthio)quinazolin-4- yl)benzohydrazide NA NA14.7 149

  2-fluoro-N′-(2- (trifluoromethyl)quinazolin-4-yl)-N′-methylbenzohydrazide NA NA 13.7 184

  4-fluoro-N′-methyl-N′-(2- (methylthio)quinazolin-4- yl)benzohydrazideNA NA 13.8 290

  N′,3-dimethyl-N′-(2- (methylthio)quinazolin-4- yl)benzohydrazide NA NA12.7  46

  N′-(2- (trifluoromethyl)quinazolin-4- yl)-4-methoxy-N′-methylbenzohydrazide NA NA 13.1  39

Thus, (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine(Example 1) and analogs are identified as potent caspase cascadeactivators and inducers of apoptosis and are thus useful in treating thevarious diseases and disorders discussed above.

EXAMPLE 144 Identification of(2-Chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine and Analogsas Antineoplastic Compounds that Inhibit Cell Proliferation (GI₅₀)

T-47D, DLD, H1299, MX-1 and SW620 cells were grown and harvested as inExample 143. An aliquot of 90 μL of cells (4.4×10⁴ cells/mL) was addedto a well of a 96-well microtiter plate containing 5 μL of a 10% DMSO inRPMI-1640 media solution containing 10 nM to 100 μM of(2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (1 nM to 10μM final). An aliquot of 45 μL of cells was added to a well of a 96-wellmicrotiter plate containing 5 μL of a 10% DMSO in RPMI-1640 mediasolution without compound as the control sample for maximal cellproliferation (L_(Max)). The samples were mixed by agitation and thenincubated at 37° C. for 48 h in a 5% CO₂-95% humidity incubator. Afterincubation, the samples were removed from the incubator and 25 μL ofCellTiter-Glo™ reagent (Promega) was added. The samples were mixed byagitation and incubated at room temeperature for 10-15 min. Plates werethen read using a luminescent plate reader (Model SPECTRAfluor Plus,Tecan) to give L_(test) values.

Baseline for GI₅₀ (dose for 50% inhibition of cell proliferation) ofinitial cell numbers was determined by adding an aliquot of 45 μL ofcells or 45 μL of media, respectively, to wells of a 96-well microtiterplate containing 5 μL of a 10% DMSO in RPMI-1640 media solution. Thesamples were mixed by agitation and then incubated at 37° C. for 0.5 hin a 5% CO₂-95% humidity incubator. After incubation, the samples wereremoved from the incubator and 25 μL of CellTiter-Glo™ reagent (Promega)was added. The samples were mixed by agitation and incubated at 37° C.for 10-15 min at room temperatur in a 5% CO₂-95% humidity incubator.Fluorescence was read as above, (L_(Start)) defining luminescence forinitial cell number used as baseline in GI₅₀ determinations.

Calculation:

GI₅₀ (dose for 50% inhibition of cell proliferation) is theconcentration where [(L_(Test)−L_(Start))/(L_(M)−L_(Start))=0.5.

The GI₅₀ (nM) are summarized in Table II:

TABLE II GI₅₀ in Cancer Cells GI₅₀ (nM) Cell lines Example 1 Example 7Example 34 Example 36 T-47D 8 >10000 503 111 DLD 8 >10000 76 89 H12996 >10000 59 53 MX-1 5 >10000 73 73 SW620 3 >10000 55 70

EXAMPLE 145 Identification of(2-Chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine and Analogsas Inhibitors of Tubulin Polymerization

Lyophilized tubulin (Cytoskeleton #ML113, 1 mg, MAP-rich) was assayedfor the effect of the test compound on tubulin polymerization asmeasured by change in fluorescence for 4′,6-diamidino-2-phenylindole(DAPI) (Barron, D. M. et al. Analytical Biochem., 2003, 315, 49-56.). 1μl of serial dilutions of each test compound (from 100× DMSO stock) wasadded in 96 well plate format and preincubated for 30 minutes with 94 ulof the non-GTP supplemented tubulin supernatant. 5 μl of DAPI/GTPsolution was added to initiate polymerization and incubated for 30minutes at 37° C. Fluorescence was read with excitation 350 nm, emissionwavelength 485 nm on a Tecan Spectraflour Plus. Polymerized tubulin(DMSO and with the tubulin stabilizer taxol® (paclitaxel)) gives ahigher DAPI fluorescence as compared to non-polymerized tubulin(vinblastine and colchicine used to determine baseline). The IC₅₀ fortubulin inhibition was the concentration found to decrease thefluorescence of DAPI by 50% as calculated with Prism 3.0. The IC50 aresummarized in Table III.

TABLE III Inhibition of Tubulin Polymerization Activity Inhibition oftubulin Caspase activation polymerization Example (EC₅₀ nM) (IC₅₀, nM) 12 <500 2 31 3000 6 219 4000 7 >10000 >50000 12 8 2000 13 260 6000 20 1613000 25 42 2000 31 317 10000 34 7 1000 35 141 4000 36 6 <1000 41 20<1000 42 282 5000 43 34 2000 44 501 10000 65 599 10000 72 2 <1000

Thus, (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine(Example 1) and analogs are identified as potent inhibitors of tubulinpolymerization and are thus useful in treating diseases and disordersdiscussed above.

EXAMPLE 146 Identification of(2-Chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine as aCytotoxic Compound in Multidrug Resistant Cells

Cytotoxicity of compounds in multidrug resistant cells can be determinedby administering compounds to cell lines that overexpress the multidrugresistance pump MDR-1 and determining the viability of the cell lines.NCI-ADR/Res and P388/ADR cell lines are known to over-express themultidrug resistance pump MDR-1 (also known as P-glycoprotein-1; Pgp-1);whereas MCF-7 and P388 cell lines do not overexpress the multidrugresistance pumps MDR-1, MRP-1, or BCRP.

NCI-ADR/Res, MCF-7, P388, and P388/ADR cell lines were obtained fromAmerican Type Culture Collection (Manassas, Va.) and maintained inRPMI-1640 media supplemented with 10% FCS, 10 units/ml penicillin andstreptomycin, 2 mM Glutamax and 1 mM sodium pyruvate (InvitrogenCorporation, Carlsbad, Calif.). For compound testing, cells were platedin 96 well dishes at a concentration of 1.5×10⁴ cells/well. Cells wereallowed to adhere to the plate overnight and then incubated withcompounds at final concentrations ranging from 0.13 nM to 10 uM for 72hours. Cell viability was then assessed using the ATP-lite reagent(Perkin Elmer, Foster City, Calif.). Plates were read on a WallacTopcount luminescence reader (Perkin Elmer, Foster City, Calif.) and theresults graphed in Prism software (Graphpad Software, Inc., San Diego,Calif.). Non-linear regression with variable slope analysis wasperformed to obtain IC₅₀ concentration values.

Example 1 compound, docetaxel, and vinblastine were tested for theirability to kill multidrug resistant cells by administering the compoundsto NCI-ADR/Res, MCF-7 cells, P388 and P388/ADR cells and determining theviability of the cells. Example 1 compound maintained nearly equalpotency in all four cell lines, whereas known MDR-1 substratesvinblastine and docetaxel showed a loss of potency in the MDR-1over-expressing cell lines as shown in Table IV below:

TABLE IV Cytotoxicity of Exa 1 Cmpd in MDR-1 over-expressing cell linesIC₅₀ (nM) Cell Line Exa 1 Cmpd Vinblastine Docetaxel MCF-7 2.9 0.5 2NCI/ADR-RES 1.3 3 410 P388 1.1 2.6 7 P388/ADR 2.7 2.8 127

Thus, (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine isidentified as a cytotoxic compound in multidrug resistant cells and isthus useful in treating diseases and disorders discussed above.

EXAMPLE 147 Propidium Iodide and Annexin V Flow Cytometer-Based Assay ToDetect Apoptosis

Necrotic versus apoptotic killing of human cell lines by compounds canbe determined using dual annexin V-FITC and propidium iodide (PI)staining. Flipping of phosphatidylserine to the outer leaflet of theplasma membrane is a characteristic of all apoptotic cells. AnnexinV isa serum protein that binds to phosphatidylserine in the presence of thedivalent cations (calcium). PI is a DNA stain that is excluded from livecells and is used to discriminate between cells with intact or damagedplasma membranes.

Cells are plated at varying densities in 6 well plates and treated withvarying concentrations of compounds for 18-72 hours. Cells are grown inRPMI-1640 media supplemented with 10% FCS. DMSO concentrations do notexceed 0.1% v:v in any assay. All cells in the wells are harvested andrinsed 1× with cold Hanks buffered saline solution (HBSS) containingcalcium and magnesium (Invitrogen, Carlsbad Calif.). Carefully aspiratesupernatant after the wash and resuspend in 100 μl Annexin V-FITC(Annexin V/PI Apoptosis Detection Kit; R & D Systems TA4638;Minneapolis, Minn.) in binding buffer (10 mM HEPES pH 7.4, 150 mM NaCl,5 mM KCl, 1 mM MgCl₂, 1.8 mM CaCl₂ and 2% bovine serum albumin w:v).Incubate in dark for 15 minutes on ice. Prior to analyzing samples, thevolume is adjusted to 500 μl with 1× Binding Buffer and 25 μl PI isadded per sample. Staining can be quantified on a flow cytometer(Becton-Dickenson, Franklin Lake, N.J.).

EXAMPLE 148 Injection Formulation

Excipients Amount Active Compound 5 mg PEG-400 5 grams TPGS 10 gramsBenzyl alcohol 0.5 gram Ethanol 2 grams D5W Add to make 50 mL

An injection formulation of a compound selected from Formula IV (the“Active Compound”) can be prepared according to the following method. 5mg of the Active Compound is dissolved into a mixture of thed-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), PEG-400,ethanol, and benzyl alcohol. D5W is added to make a total volume of 50mL and the solution is mixed. The resulting solution is filtered througha 0.2 μm disposable filter unit and is stored at 25° C. Solutions ofvarying strengths and volumes are prepared by altering the ratio ofActive Compound in the mixture or changing the total amount of thesolution.

EXAMPLE 149 Tablet Formulation

Active Compound 100.0 mg Lactose 100.0 mg Corn Starch  50.0 mgHydrogenated Vegetable Oil  10.0 mg Polyvinylpyrrolidone  10.0 mg 270.0mg

A formulation of tablets of a compound selected from Formulae I-VIb(e.g. Example 1 compound) (the “Active Compound”) can be preparedaccording to the following method. 100 mg of Active Compound) is mixedwith 100 mg lactose. A suitable amount of water for drying is added andthe mixture is dried. The mixture is then blended with 50 mg of cornstarch, 10 mg hydrogenated vegetable oil, and 10 mgpolyvinylpyrrolidinone. The resulting granules are compressed intotablets. Tablets of varying strengths are prepared by altering the ratioof Active Compound in the mixture or changing the total weight of thetablet.

EXAMPLE 150 Capsule Formulation

Active Compound 100.0 mg Microcrystalline Cellulose 200.0 mg Corn Starch100.0 mg Magnesium Stearate 400.0 mg 800.0 mg

A formulation of capsules containing 100.0 mg of a compound selectedfrom Formulae I-VIb (e.g. Example 1 compound) (the “Active Compound”)can be prepared according to the following method. 100 mg of ActiveCompound is mixed with with 200 mg of microcrystalline cellulose and 100mg of corn starch. 400 mg of magnesium stearate is then blended into themixture and the resulting blend is encapsulated into a gelatin capsule.Doses of varying strengths can be prepared by altering the ratio of theActive Compound to pharmaceutically acceptable carriers or changing thesize of the capsule.

EXAMPLE 151 Identification of(2-Chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine as anInhibitor of Topoisomerase

The ability of compounds to inhibit Topoisomerase II activity inrelaxing supercoiled DNA can be determined by adding compounds to DNAsamples and measuring the formation of topoisomers. The addition ofTopoisomerase II to DNA samples results in the formation of topoisomers,which migrate faster than open circular DNA and slower than supercoiledDNA substrate when run on a gel. Ethidium Bromide, a known intercalator,and etoposide (VP16), a known topoisomerase II inhibitor, are used ascontrols.

Assay reagents were obtained from TopoGEN, Inc. (Columbus, Ohio).Samples were prepared by combining 10 μl of D/W, 2 μl of 10× TOPO IIassay buffer, and 1 μl (0.25 μg) pRYG DNA. 5 μl of(2-Chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (Example 1Compound), Ethidium Bromide, or VP16 were added to samples at varyingconcentrations. 2 μl of TOPO II (4 units in 20 μl reaction) was added tothe samples and the samples were incubated at 37° C. in a water bath for50 minutes. 2 μl of 10% SDS was added and 0. Proteinase K (500 μg/ml)was added and the samples were incubated again at 37° C. in a water bathfor 50 minutes. Half of the reaction was loaded on a 1% gel withoutethidium bromide and run in 1×TAE buffer at 20 volts/cm for 2 hours. Thegel was stained with 0.5 μg/ml Ethidium Bromide for 10 seconds anddestained in D/W for 30 seconds. The resulting gel image is shown inFIG. 1.

Inspection of the amount of supercoiled DNA present in the sample with100 μM of Example 1 Compound indicates that inhibition of DNA relaxationis substantial. The results are consistent with topoisomerase IIinhibition as well as with an effect of the compound not ontopoisomerase II, but rather on the DNA itself, such as intercalation ofthe compound into the DNA substrate. In order to distinguish betweendirect inhibition of topoisomerase II activity and intercalation, theeffect of Example 1 Compound is determined on topoisomerase I-mediatedrelaxation of supercoiled DNA.

Samples were prepared by combining 10 μl of D/W, 2 μl of 10× TOPO IIassay buffer, and 1 μl (0.25 μg) Form I DNA. 5 μl of(2-Chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (Example 1Compound), Ethidium Bromide, or VP16 were added to samples at varyingconcentrations. 1 μl of TOPO I (5 units in 20 μl reaction) was added tothe samples and the samples were incubated at 37° C. in a water bath for50 minutes. 2 μl of 10% SDS was added and 0. Proteinase K (500 μg/ml)was added and the samples were incubated again at 37° C. in a water bathfor 50 minutes. Half of the reaction was loaded on a 1% gel withoutethidium bromide and run in 1×TAE buffer at 20 volts/cm for 2 hours. Thegel was stained with 0.5 μg/ml Ethidium Bromide for 10 seconds anddestained in D/W for 30 seconds. The resulting gel image is shown inFIG. 2.

As shown in FIG. 2, the known intercalator, Ethidium Bromide, completelyeliminated topoisomerase I-dependent relaxation of supercoiled DNA, justas it eliminated topoisomerase II-dependent relaxation of supercoiledDNA (see FIG. 1). In contrast, Example 1 Compound and the knowntopoisomerase II inhibitor, VP-16, have no apparent effect ontopoisomerase I activity.

EXAMPLE 152 Identification of Radiolabeled(4-Azido-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine as an Inhibitorof Topoisomerase

30 Units (15 ul) Human Type II Topoisomerase (p170 Form) (from TopoGEN,Inc., Columbus, Ohio) was incubated with 50 nM radiolabeled Example 102compound for 60 minutes at room temperature.

Radiolabeled Example 102 Compound

(Radiolabeled Example 102 compound stock is 16.67 uM, 60 Ci/mmol, 1mCi/m1 American Radiolabeled Chemicals, Inc., St. Louis, Mo. Sampleswere either UV irradiated (+) with a short wavelength UV Source (254 nm)for 10 minutes at a distance of 3.5 cm or not irradiated (−). 8 μl of 5×sample buffer (150 mM Tris, pH 6.8, 50% glycerol, 1% SDS, 50 mMdithiothreitol, 62 mg/ml bromophenol blue) was added to the samples andboiled for 5 minutes. The entire sample was then loaded onto a 6%Tris-Glycine SDS-gel (10 well, 1.5 mm thickness) (Invitrogen, Carlsbad,Calif.). The gel was stained with 1% Coomassie Brilliant Blue in 40%methanol, 7.5% acetic acid for 2 hours then de-stained in severalchanges of de-stainer (40% methanol, 7.5% acetic acid). The gel was thenincubated in Amplify (Amersham, Piscataway, N.J.) for 30 minutes at roomtemperature and then dried down on Whatman filter paper at 80° C. for 2hours on a gel dryer. The dried gel was put on Hyperfilm (Amersham) in afilm cassette and placed at 80° C. for 5-7 days. The resulting gel imageis shown in FIG. 3. These results indicate that the compound bindssufficiently well to Topoisomerase II to crosslink to the enzyme whenphotoactivated.

Having now fully described this invention, it will be understood bythose of ordinary skill in the art that the same can be performed withina wide and equivalent range of conditions, formulations and otherparameters without affecting the scope of the invention or anyembodiment thereof. All patents, patent applications and publicationscited herein are fully incorporated by reference herein in theirentirety.

1-54. (canceled).
 55. A compound according to Formula Vlb:

or pharmaceutically acceptable salts thereof, wherein: R₁ is methyl orethyl; R₅ is H or F; R₂ is halo, N₃, OH, thiol, nitro, CN, NH₂, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ alkylthiol,halo-C₁₋₆ alkyl, C₂₋₆ alkenyl-O—, C₂₋₆ alkynyl-O, hydroxy-C₁₋₆ alkyl,C₁₋₆ alkoxy-C₁₋₆ alkyl, C₁₋₆ acyl, C₁₋₆ acyloxy, C₁₋₆ alkyl-C(O)O—C₁₋₆alkyl, —C(O)O—C₁₋₆ alkyl, C₁₋₆ alkyl-C(O)O—C₁₋₆ alkyl, C₁₋₆ acylamido,—N(R^(a))(R^(b)), —C₁₋₆ alkyl-C(O)N(R^(a))(R^(b)), —C(O)N(R^(a))(R^(b)),N(R^(a))(R^(b))-C₁₋₆ alkyl-, 3, 4, 5, or 6-membered carbocycle,heterocycle, or heteroaryl, wherein R^(a) and R^(b) are independently H,OH (R^(a) and R^(b) are not both OH), C₂₋₆ hydroxyalkyl, or C₁₋₆ alkyl,or R^(a) and R^(b) together with the nitrogen atom to which they areboth linked form a 3, 4, 5 or 6-membered heterocycle; wherein any of thegroups is optionally substituted with 1-3 substituents wherein eachsubstituent is independently halo, N₃, OH, thiol, nitro, CN, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ alkylthiol, C₂₋₆alkenyl-O-, C₂₋₆ alkynyl-O-, hydroxy-C₁₋₆ alkyl, C₁₋₆ alkoxy-C₁₋₆ alkyl,C₁₋₆ acyl, C₁₋₆ acyloxy, C₁₋₆ alkyl-C(O)O—C₁₋₆ alkyl-, C₁₋₆ acylamido,—N(R^(a))(R^(b)), —C₁₋₆ alkyl-C(O)N(R^(a))(R^(b)), —C(O)N(R^(a))(R^(b)),N(R^(a))(R^(b))—C₁₋₆ alkyl-, wherein R^(a) and R^(b) are independentlyH, OH (R^(a) and R^(b) are not both OH), C₂₋₆ hydroxyalkyl, or C₁₋₆alkyl or R^(a) and R^(b) together with the nitrogen atom to which theyare both linked form a 3, 4, 5 or 6-membered heterocycle; and R₃, R₄,and R₆-R₁₁ are independently H, halo, N₃, OH, thiol, nitro, CN, NH₂,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ alkylthiol,halo-C₁₋₆ alkyl, C₂₋₆ alkenyl-O—, C₂₋₆ alkynyl-O—, hydroxy-C₁₋₆ alkyl,C₁₋₆ alkoxy-C₁₋₆ alkyl, C₁₋₆ acyl, C₁₋₆ acyloxy, —C₁₋₆ alkyl-C(O)O—C₁₋₆alkyl, —C(O)O—C₁₋₆ alkyl, C₁₋₆ alkyl-C(O)O—C₁₋₆ alkyl-, C₁₋₆ acylamido,—N(R^(a))(R^(b)), —C₁₋₆ al kyl-C(O)N(R^(a))(R^(b)),—C(O)N(R^(a))(R^(b)), N(R^(a))(R^(b))-C₁₋₆ alkyl, 3, 4, 5, or 6-memberedcarbocycle, heterocycle, aryl, or heteroaryl, wherein R^(a) and R^(b)are independently H, OH (R^(a) and R^(b) are not both OH), C₂₋₆hydroxyalkyl, or C₁₋₆ alkyl, or R^(a) and R^(b) together with thenitrogen atom to which they are both linked form a 3, 4, 5 or 6-memberedheterocycle; wherein any of the groups is optionally substituted with1-3 substituents wherein each substituent is independently halo, N₃, OH,thiol, nitro, CN, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy,C₁₋₆ alkylthiol, C₂₋₆ alkenyl-O—, C₂₋₆ alkynyl-O—, hydroxy-C₁₋₆ alkyl,C₁₋₆ alkoxy-C₁₋₆ alkyl, C₁₋₆ acyl, C₁₋₆ acyloxy, C₁₋₆ alkyl-C(O)O—C₁₋₆alkyl-, C₁₋₆ acylamido, —N(R^(a))(R^(b)), —C₁₋₆alkyl-C(O)N(R^(a))(R^(b)), —C(O)N(R^(a))(R^(b)), N(R^(a))(R^(b))—C₁₋₆alkyl-, wherein R^(a) and R^(b) are independently H, OH (R^(a) and R^(b)are not both OH), C₂₋₆ hydroxyalkyl, or C₁₋₆ alkyl or R^(a) and R^(b)together with the nitrogen atom to which they are both linked form a 3,4, 5 or 6-membered heterocycle, wherein optionally any two adjacentR₇-R₁₁ groups together form a 3, 4, 5 or 6-membered carbocycle orheterocycle; provided that R₉ is not —O(C₁₋₆ alkyl)C(O)O(C₁₋₆ alkyl),and when R₉ is H then R₈ and R₁₀ are not both H or one H and the otherhalo.
 56. The compound of claim 55, wherein when R₉ is H then at leastone of R₈ and R₁₀ is not H or halo or C₁₋₆ alkyl.
 57. The compound ofclaim 55, wherein R₉ is selected from the group consisting of H, Cl, N₃,C₁₋₆ alkyl optionally substituted with 1, 2 or 3 substituents, eachsubstituent being independently OH, halo, C₁₋₃ alkoxy, (halo)C₁₋₃alkoxy, —N(R^(a))(R^(b)) where R^(a) and R^(b) are independently H, OH(R^(a) and R^(b) are not both OH), C₂₋₄ hydroxyalkyl, or C₁₋₃ alkyl orR^(a) and R^(b) together with the nitrogen atom to which they are bothlinked form a 3, 4, 5 or 6-membered heterocycle; —XR^(c) wherein X is Sor O and R^(c) is C₁₋₆ alkyl optionally substituted with 1, 2 or 3substituents, each substituent being independently OH, halo, C₁₋₃alkoxy, or (halo)C₁₋₃ alkoxy; —(C₀₋₃ alkyl)CO₂R^(d) where R^(d) is C₁₋₆alkyl; —N(R^(a))(R^(b)) where R^(a) and R^(b) are independently H, OH(R^(a) and R^(b) are not both OH), C₂₋₄ hydroxyalkyl, C₁₋₃ alkyl, or—N(R^(e))(R^(f)) where R^(e) and R^(f) are independently H, OH (R^(c)and R^(f) are not both OH), or C₁₋₃ alkyl; wherein optionally R^(a) andR^(b) together with the nitrogen atom to which they are both linked forma 3, 4, 5 or 6-membered heterocycle, and optionally le and R^(f)together with the nitrogen atom to which they both are linked form a 3,4, 5 or 6-membered heterocycle; and —(Co₋₃ alkyl)C(O)N(R^(a))(R^(b))where R^(a) and R^(b) are independently H or C₁₋₃ alkyl; and optionallyR₉ and one of R₈ and R₁₀ together form a 3, 4, 5, or 6-memberedheterocycle.
 58. The compound of claim 55, wherein R₉ is H; OH; Cl; N₃;C₁₋₃ alkyl; C₁₋₃ haloalkyl; —OR_(9a) where R_(9a) is C₁₋₄ alkyl or C₁₋₃haloalkyl; —NH(R^(a)) or —N(R^(a))(R^(b)) where R^(a) and R^(b) areindependently C₁₋₃ alkyl; or —COOR_(9b) where R_(9b) is C₁₋₃ alkyl; andoptionally R₉ and one of R₈ and R₁₀ together form a 3, 4, 5, or6-membered heterocycle.
 59. The compound of claim 55, wherein when R₉ isH, then R₈ or R₁₀ or both are independently OH; N₃; —XR_(9a), where X isO or S and R_(9a) is C₁₋₄ alkyl or C₁₋₃ haloalkyl; —NH(R^(a)) or—N(R^(a))(R^(b)) where R^(a) and R^(b) are independently C₁₋₃ alkyl; or—COOR_(9b) wherein R_(9b) is C₁₋₃ alkyl.
 60. The compound of claim 55,wherein when R₉ is H, then R₈ or R₁₀ or both are independently N₃;—OR_(9a) where R_(9a) is C₁₋₄ alkyl or C₁₋₃ haloalkyl; —N(R^(a))(R^(b))where R^(a) and R^(b) are independently C₁₋₃ alkyl; or —COOR_(9b) whereR_(9b) is C₁₋₃ alkyl.
 61. The compound of claim 55, wherein when R₈ isH, then R₈ or R₁₀ or both are C₁₋₃ alkoxy or C₁₋₃ halo alkoxy.
 62. Thecompound of claim 55, wherein R₉ is N₃; —OR_(9a), wherein R_(9a) is C₁₋₃alkyl optionally substituted with 1-7 F; —N(R^(a))(R^(b)) where R^(a)and R^(b) are independently C₁₋₃ alkyl; or —COOR_(9b) where R_(9b) isC₁₋₃ alkyl.
 63. The compound of claim 55, wherein R₁ is CH₃; R₂ ismethyl, ethyl, Cl, F, fluoromethyl, CH₂OH, NH₂, NHCH₃, N(CH₃)₂,—NHCH₂CH₂OH, OCH₃, or SCH₃; R₃ is H, CH₃, OCH₃, F, or Cl; R₄ and R₆ areindependently H, CH₃, NH₂, F, or Cl; R₅ is H; R₇ and R₁₁ areindependently H, F, or OCH₃; R₈ and R₁₀ are independently H, F, Cl, orOCH₃; and R₉ is selected from the group consisting of —OR₁₂ where R₁₂ ismethyl, ethyl, fluoromethyl or fluoroethyl, —NHCH₃, N(CH₃)₂, N₃, and—COOR_(D) where R₁₃ is methyl or ethyl.
 64. A compound according toFormula VIb:

or pharmaceutically acceptable salts thereof, wherein: R₁ is methyl orethyl; R₅ is H or F; R₂-R₄, R₆-R₁₁ are independently H, halo, N₃, OH,thiol, nitro, CN, NH₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆alkoxy, C₁₋₆ alkylthiol, halo-C₁₋₆ alkyl, C₂₋₆ alkenyl-O—, C₂₋₆alkynyl-O—, hydroxy-C₁₋₆ alkyl, C₁₋₆ alkoxy-C₁₋₆ alkyl, C₁₋₆ acyl, C₁₋₆acyloxy, —C₁₋₆ alkyl-C(O)O—C₁₋₆ alkyl, —C(O)O—C₁₋₆ alkyl, C₁₋₆alkyl-C(O)O—C₁₋₆ alkyl-, C₁₋₆ acylamido, —N(R^(a))(R^(b)), —C₁₋₆alkyl-C(O)N(R^(a))(R^(b)), —C(O)N(R^(a))(R^(b)), N(R^(a))(R^(b))—C₁₋₆alkyl-, 3, 4, 5, or 6-membered carbocycle, heterocycle, or heteroarylwherein R^(a) and R^(b) are independently H, OH (R^(a) and R^(b) are notboth OH), C₂₋₆ hydroxyalkyl, or C₁₋₆ alkyl, or R^(a) and R^(b) togetherwith the nitrogen atom to which they are both linked form a 3, 4, 5 or6-membered heterocycle; wherein any of the groups is optionallysubstituted with 1-3 substituents wherein each substituent isindependently halo, N₃, OH, thiol, nitro, CN, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ alkylthiol, C₂₋₆ alkenyl-O—, C₂₋₆alkynyl-O—, hydroxy-C₁₋₆ alkyl, C₁₋₆ alkoxy-C₁₋₆ alkyl, C₁₋₆ acyl, C₁₋₆acyloxy, C₁₋₆ alkyl-C(O)O—C₁₋₆ alkyl-, C₁₋₆ acylamido, —N(R^(a))(R^(b)),—C₁₋₆ alkyl-C(O)N(R^(a))(R^(b)), —C(O)N(R^(a))(R^(b)),N(R^(a))(R^(b))-C₁₋₆ alkyl-, wherein R^(a) and R^(b) are independentlyH, OH (R^(a) and R^(b) are not both OH), C₂₋₆ hydroxyalkyl, or C₁₋₆alkyl or R^(a) and R^(b) together with the nitrogen atom to which theyare both linked form a 3, 4, 5 or 6-membered heterocycle, whereinoptionally any two adjacent R₇-R₁₁ groups together form a 3, 4, 5 or6-membered carbocycle or heterocycle; provided that R₉ is H; OH; Cl; N₃;C₁₋₃ alkyl; C₁₋₃ haloalkyl; —OR_(9a) where R_(9a) is C₁₋₄ alkyl or C₁₋₃haloalkyl; —NH(R^(a)) or —N(R^(a))(R^(b)) where R^(a) and R^(b) areindependently C₁₋₃ alkyl; or —COOR_(9b) where R_(9b) is C₁₋₃ alkyl; andoptionally R₉ and one of R₈ and R₁₀ together form a 3, 4, 5, or6-membered heterocycle; and provided that when R₉ is H then R₈ and R₁₀are not both H or one H and the other halo.
 65. The compound of claim64, wherein: R₂ is H; halo; N₃, C₁₋₆ alkyl optionally substituted with1-4 substituents which are independently OH or halo; —XR_(2a) where X isS or O, and R_(2a) is C₁₋₆ alkyl optionally substituted with OH or halo;—CO₂—R_(2f), where R_(2f) is C₁₋₆; or —N(R_(2b))(R_(2c)) where R_(2b)and R_(2c) are independently H, OH, C₁₋₆ alkyl, C₁₋₆ hydroxyalkyl, orC₁₋₆ alkyl that is optionally substituted with —N(R_(2a))(R_(2e)) whereR_(2d) and R_(2e) are independently H, OH, C₁₋₃ alkyl, or C₂₋₃hydroxyalkyl, and wherein R_(2b) and R_(2c) together with the nitrogenatom to which they are both linked may form a 3, 4, 5 or 6-memberedheterocycle, and wherein R_(2b) and R_(2c) are not both OH, R_(2d) andR_(2e) are not both OH; R₃ is H; halo; C₁₋₃ alkyl; or C₁₋₃ alkoxy; R₄and R₆ are independently H; halo; N₃ C₁₋₃ alkyl; C₁₋₃ alkoxy; or—N(R_(2b))(R_(2c)) wherein R_(2b) and R_(2c) are independently H, OH,CH3, and optionally R_(2b) and R_(2c) together may form a 3, 4, 5 or6-membered heterocycle, and where R_(2b) and R_(2c) are not both OH; R₅is H; R₇ and R₁₁ are independently H, halo, CH₃, or OCH₃; R₈ and R₁₀ areindependently H; halo; C₁₋₃ alkyl; C₁₋₃ alkoxy; —XR_(9a), where X is Oor S, and R₉a is C₁₋₄ alkyl or C₁₋₃ haloalkyl; —N(R^(a))(R^(b)) whereR^(a) and R^(b) are independently C₁₋₃ alkyl; or —COOR_(9b), whereinR_(9b) is C₁₋₃ alkyl; and R₉ is selected from the group consisting of H;hydroxy; Cl; N₃; C₁₋₃ alkyl or C₁₋₃ haloalkyl; —OR_(9a), wherein R₁₂ isC₁₋₃ alkyl or C₁₋₃ haloalkyl; —N(R_(2b))(R_(2c)) where R_(2b) and R_(2c)are independently H, C₁₋₃ alkyl, or C₁₋₃ haloalkyl; or —COOR_(9b),wherein R_(9b) is C₁₋₃ alkyl; and optionally R₉ and one of R_(g) and R₁₀together form a 3, 4, 5, or 6-membered heterocycle.
 66. The compound ofclaim 64, wherein: R₂ is H; halo; N₃, C₁₋₆ alkyl optionally substitutedwith 1-4 substituents that are OH or halo; —XR_(2a) where X is S or O,and R_(2a) is C₁₋₆ alkyl optionally substituted with OH or halo; or—N(R_(2b))(R_(2c)) where R_(2b) and R_(2c) are independently H, OH, C₁₋₆alkyl, C₁₋₆ hydroxyalkyl, or R_(2b) and R_(2c) together with thenitrogen atom to which they are both linked form a 3, 4, 5 or 6-memberedheterocycle; R₃ is H; halo; C₁₋₃ alkyl; or C₁₋₃ alkoxy; R₄ and R₆ areindependently H; halo; N₃, C₁₋₃ alkyl; C₁₋₃ alkoxy; or—N(R_(2b))(R_(2c)) wherein R_(2b) and R_(2c) are independently H, OH(R_(2b) and R_(2c) are not both OH), CH₃, or R_(2b) and R_(2c) togetherform a 3, 4, 5 or 6-membered heterocycle; R₅ is H; R₇, R₈, R₁₀ and R₁₁are independently H, halo, C₁₋₃ alkyl, C₁₋₃ alkoxy, or C₁₋₃ alkylthiol;R₉ is selected from the group consisting of H; OH; Cl; N₃; C₁₋₃ alkyl;C₁₋₃ haloalkyl; —OR_(9a) where R_(9a) is C₁₋₃ alkyl or C₁₋₃ haloalkyl;N(R_(2b))(R_(2c)) where R_(2b) and R_(2c) are independently C₁₋₃ alkyl;or —COOR_(9b) where R_(9b) is C₁₋₃ alkyl; and optionally R₉ and one ofR₈ and R₁₀ together form a 3, 4, 5, or 6-membered heterocycle.
 67. Thecompound of claim 64, wherein R₁ is methyl or ethyl; R₂ is H, methyl,ethyl, Cl, F, fluoromethyl, C₁₋₃ hydroxyalkyl, NH₂, NH₂OH, NHCH₂CH₂OH,NHCH₃, N(CH₃)₂, N₃, morpholino, OCH₃, OC₂H₅, or SCH₃; R₃ is H, CH₃,OCH₃, F, or Cl; R₄ and R₆ are independently H, CH₃, NH₂, N₃, F, or Cl;R₅ is H; R₇ and R₁₁ are independently H, F, or OCH₃; R_(g) and R₁₀ areindependently H, F, Cl, or OCH₃; and R₉ is selected from the groupconsisting of H, OH, N₃, Cl, C₁₋₃ alkyl, C₁₋₃ haloalkyl, or —OR_(9a)where R_(9a) is C₁₋₃ alkyl or C₁₋₃ haloalkyl, —N(R_(2b))(R_(2c)) whereinR_(2b) and R_(2c) are independently C₁₋₃ alkyl, or —COOR_(9b) whereR_(9b) is C₁₋₃ alkyl, and optionally R₈ and R₉ together form a 3, 4, 5,or 6-membered heterocycle; provided that when R₉ is H, at least one ofR₈ and R₁₀ is OCH₃, and when R₉ is C₁₋₃ alkyl or C₁₋₃ haloalkyl or Cl,R₂ is Cl or methyl or ethyl.
 68. The compound of claim 64, wherein R₂ isH; halo; N₃, C₁₋₆ alkyl optionally substituted with OH or halo; —XR_(2a)wherein X is S or O, and R_(2a) is C₁₋₆ alkyl optionally substitutedwith OH or halo; —CO₂R^(d) wherein R^(d) is C₁₋₃ alkyl; or—N(R^(a))(R^(b)) wherein R^(a) and R^(b) are independently H, OH (R^(a)and R^(b) are not both OH), C₁₋₆ alkyl, C₁₋₆ hydroxyalkyl, or C₁₋₆ alkylthat is optionally substituted with —N(R^(e))(R^(f)) wherein R^(e) andR^(f) are independently H, OH (R^(e) and R^(f) are not both OH), C₁₋₃alkyl, or C₂₋₃ hydroxyalkyl, and wherein optionally R^(a) and R^(b)together with the nitrogen atom to which they are both linked may form a3, 4, 5 or 6-membered heterocycle.
 69. The compound of claim 64, whereinR₂ is H; halo; C₁₋₃ alkyl optionally substituted with OH or halo;—XR_(2a) wherein X is S or O and R_(2a) is C₁₋₃ alkyl optionallysubstituted with halo; or —N(R^(a))(R^(b)) wherein R^(a) and R^(b) areindependently H, OH (R^(a) and R^(b) are not both OH), C₁₋₃ alkyl, C₂₋₃hydroxyalkyl.
 70. The compound of claim 64, wherein R₁ is CH₃; R₂ is H,methyl, ethyl, Cl, F, fluoromethyl, CH₂OH, NH₂, NHCH₃, N(CH₃)₂,—NHCH₂CH₂OH, OCH₃, or SCH₃; R₃ is H, CH₃, OCH3, F, or Cl; R₄ and R₆ areindependently H, CH₃, NH₂, F, or Cl; R₅ is H; R₇ and R₁₁ areindependently H, F, or OCH₃; R₈ and R₁₀ are independently H, F, Cl, orOCH₃; and R₉ is selected from the group consisting of —OR₁₂ where R₁₂ ismethyl, ethyl, fluoromethyl or fluoroethyl, —NHCH₃, N(CH₃)₂, N₃, and—COOR_(D) where R₁₃ is methyl or ethyl.
 71. A pharmaceutical compositioncomprising a pharmaceutically acceptable carrier and an effective amountof a compound according to claim
 55. 72. A pharmaceutical compositioncomprising a pharmaceutically acceptable carrier and an effective amountof a compound according to claim
 64. 73. A method of treating cancer,comprising treating a patient in need thereof with atherapeutically-effective amount of a compound according to claim 55.74. A method of treating cancer, comprising treating a patient in needthereof with a therapeutically-effective amount of a compound accordingto claim 64.